ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.
These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.


TagGD: fast and accurate software for DNA Tag generation and demultiplexing.
Multiplexing is of vital importance for utilizing the full potential of next generation sequencing technologies. We here report TagGD (DNA-based Tag Generator and Demultiplexor), a fully-customisable, fast and accurate software package that can generate thousands of barcodes satisfying user-defined constraints and can guarantee full demultiplexing accuracy. The barcodes are designed to minimise their interference with the experiment. Insertion, deletion and substitution events are considered when designing and demultiplexing barcodes. 20,000 barcodes of length 18 were designed in 5 minutes and 2 million barcoded Illumina HiSeq-like reads generated with an error rate of 2% were demultiplexed with full accuracy in 5 minutes. We believe that our software meets a central demand in the current high-throughput biology and can be utilised in any field with ample sample abundance. The software is available on GitHub (https://github.com/pelinakan/UBD.git).


Review article: what do patients with inflammatory bowel disease want for their clinical management?
The patient's perceptions of benefits and risks of treatment differ from those of physicians, yet this topic is rarely explored in ulcerative colitis or Crohn's disease. To present a patient's perspective on care for their colitis, to consider how patients' views will influence preliminary proposals for standards of care, and to discuss the different priorities of patients and physicians. Description of an individual patient's journey from diagnosis of ulcerative colitis to colectomy, compared with priorities proposed by a patient-based organization (National Association of Colitis and Crohn's disease). Awareness of colitis in primary care, prompt referral, timely investigation and specialist care if admitted to hospital are shared goals of patients and physicians. Patients are generally prepared to accept higher risks from medical treatment to avoid their undesirable outcomes (especially colectomy) than physicians will on their behalf. There has been little systematic study of this disparity in ulcerative colitis. Under-reporting the symptom burden, tolerance of treatment side effects, substantial lifestyle changes and willingness to explore any treatment options are characteristic coping strategies. Physicians should be alert to coping strategies, with a willingness to seek second opinions. Perceptions of risk and benefit differ between patients and physicians, and recognition of this difference is a starting point for difficult clinical decision-making.


A new method of estimating prevalence of childhood cancer survivors (POCCS): example of the 20-year prevalence in The Netherlands.
Estimating the number of childhood cancer survivors is crucial for cancer control, including clinical guidelines. To compare estimates across countries despite data sharing restrictions, we propose a new method of computing limited-duration prevalence of childhood cancer survivors (POCCS) using aggregated data. We developed a Markov model that simulates, for each calendar year and birth cohort in a population, the proportion of individuals in the following health states: healthy, newly diagnosed with cancer, surviving with cancer, and deceased. Transitions between health states were informed using annual sex- and age-specific incidence rates, conditional 1-year net survival probabilities from the Netherlands Cancer Registry (1989-2011), and annual mortality probability by sex and age group for The Netherlands from the Human Mortality Database. Applying a Markov model, we computed 20-year prevalence of childhood cancer survivors. The resulting POCCS estimates, stratified by sex, were compared with SEER*Stat estimates derived from individual cancer records from the same registry. In 2011, POCCS predicted 654 males [95% confidence interval (95% CI): 637-672] and 539 females (95% CI: 523-555) per million persons living in The Netherlands after childhood cancer diagnosed within the previous 20 years. Using SEER*Stat, the 20-year prevalence was 665 males (95% CI: 647-683) and 544 females (95% CI: 529-560) per million persons on 1 July 2011. Using the POCCS model and aggregated cancer data, our estimates of childhood cancer survivors limited-duration prevalence were consistent with those computed by a standard method requiring individual cancer records. The POCCS method provides relevant information for planning follow-up and care for childhood cancer survivors.


BSE: can we predict the future?
Prion diseases are transmissible neurodegenerative disorders of humans and animals. The prion protein (PrPc) gene is expressed to some extent in many cell types but principally in neurons. Normal PrPc may contribute in the protection of neurons and are protease sensitive. Abnormal prions consist of a post-translationally modified form of PrP, PrPsc, which is partly protease resistant. PrPsc is a protein with high resistance to inactivation by irradiation, heat and harsh chemical treatments. It is currently proposed that PrPsc is an infectious protein that propagates by inducing the normal PrPc to become the abnormal PrPsc. PrPsc cause transmissible spongiform encephalopathies (TSE), an unusual group of degenerative brain diseases that can be transmitted by inoculation or ingestion of diseased brain or other tissues. The human diseases occur in an inherited, acquired and sporadic forms. Transmission of prion diseases between species is limited by a species barrier, determined in part by the degree of sequence homology between the host PrP and inoculated PrPsc. The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom is a new disease that has affected over 160,000 cattle and has presumably arisen from dietary exposure to PrPsc from sheep with scrapie. Until shown otherwise we must assume that oral consumption of infectious BSE protein is a new factor for Creutzfeldt-Jakob (CJD) disease in man. This disease is a new variant of CJD (nvCJD) and has a different clinical picture. Early diagnostic markers to facilitate the diagnosis and screen blood and organ donors are not available. The control of the disease relies on the measures to eradicate the spread of BSE by banning the use of ruminant tissues in ruminant feed and slaughter and rendering procedures to ensure inactivation of prions of all infected animals. The control of nvCJD is based on reduction of exposure to BSE by banning a variety of tissues for consumption. A surveillance worldwide is increased for both BSE and nv-CJD and the WHO update regularly recommendations to limit the risk of transmitting the disease. The extent and size of the nvCJD will depend on different factors among others the dose of infectious material, the route of infection, the genetic susceptibility of the person. Therefore is not possible to predict how important the disease will be.


Stochastic modelling of shifts in allele frequencies reveals a strongly polygynous mating system in the re-introduced Asiatic wild ass.
Small populations are prone to loss of genetic variation and hence to a reduction in their evolutionary potential. Therefore, studying the mating system of small populations and its potential effects on genetic drift and genetic diversity is of high importance for their viability assessments. The traditional method for studying genetic mating systems is paternity analysis. Yet, as small populations are often rare and elusive, the genetic data required for paternity analysis are frequently unavailable. The endangered Asiatic wild ass (Equus hemionus), like all equids, displays a behaviourally polygynous mating system; however, the level of polygyny has never been measured genetically in wild equids. Combining noninvasive genetic data with stochastic modelling of shifts in allele frequencies, we developed an alternative approach to paternity analysis for studying the genetic mating system of the re-introduced Asiatic wild ass in the Negev Desert, Israel. We compared the shifts in allele frequencies (as a measure of genetic drift) that have occurred in the wild ass population since re-introduction onset to simulated scenarios under different proportions of mating males. We revealed a strongly polygynous mating system in which less than 25% of all males participate in the mating process each generation. This strongly polygynous mating system and its potential effect on the re-introduced population's genetic diversity could have significant consequences for the long-term persistence of the population in the Negev. The stochastic modelling approach and the use of allele-frequency shifts can be further applied to systems that are affected by genetic drift and for which genetic data are limited.


Building primary care in Japan: Literature review.
Japan's health system is well known for achieving one of the world's highest life expectancy with universal health coverage. However, the country now faces challenges of a rapidly aging population and changes in patterns and burden of disease. Primary care is an important component of a well-functioning health system. In Japan, primary care services are provided in both the community and hospital settings. The distinction between primary and secondary care may not always be clear. This review is based on the framework from the 2015 WHO publication on primary care systems in Europe. Our aim is to describe the journey of primary care in Japan, with its past, present, and future as a valuable addition to the academic English literature. We also hope that this article would inspire readers outside of Japan who might face similar issues in their respective countries.


Potassium-argon geochronology of deep-sea sediments.
A potassitlim-argon dating method applicable to small quantities of volcanic minerals anid glass has been developed and used to determine the ages of North Pacific sediments. Tertiary sedimentation rates range from less than 1.0 millimeter per 10(3) years for deep-sea "red clay" to 1 centimeter per 10: years for calcareotus-siliceous ooze necrer the continent. The potassium-argon ages obtained from different minerals are concordaat, and in samples withl associated fossils, these ages are compatible with the paleontologic evidence.


Characteristics of Frequency Resolution and Speech Perception Using Bone Conduction on Different Human Facial Parts.
In conventional bone-conduction (BC) devices, a vibrator is typically attached to the mastoid process of the temporal bone or the condyle process of the mandible. However, BC-sound presentations to facial parts such as the nose and cheek have also been investigated recently. As the face is the among the most complex structures of the human body, transmission of sounds using BC on different facial parts are likely to show different perception and propagation characteristics than those presented to conventional parts. However, the characteristics of BC sound presented to different part of the face have not yet been studied in detail. To test the frequency discrimination ability, we measured difference limens for frequency (DLFs). We also conducted monosyllable articulation tests in Japanese to assess the speech-perception characteristics when BC sounds are presented to various facial (nasal, infraorbital region, zygomatic, jaw angle, and chin) and conventional (mastoid and condyle process) parts of a normal-hearing subject. The results suggest that, at least in the parts investigated in the current study, the frequency resolution and intelligibility of the facial parts were about the same as those of the conventional parts. These results indicate that practical frequency information and speech perception are possible with BC devices attached to different facial parts.


WT1 expression in breast cancer disrupts the epithelial/mesenchymal balance of tumour cells and correlates with the metabolic response to docetaxel.
WT1 is a transcription factor which regulates the epithelial-mesenchymal balance during embryonic development and, if mutated, can lead to the formation of Wilms' tumour, the most common paediatric kidney cancer. Its expression has also been reported in several adult tumour types, including breast cancer, and usually correlates with poor outcome. However, published data is inconsistent and the role of WT1 in this malignancy remains unclear. Here we provide a complete study of WT1 expression across different breast cancer subtypes as well as isoform specific expression analysis. Using in vitro cell lines, clinical samples and publicly available gene expression datasets, we demonstrate that WT1 plays a role in regulating the epithelial-mesenchymal balance of breast cancer cells and that WT1-expressing tumours are mainly associated with a mesenchymal phenotype. WT1 gene expression also correlates with CYP3A4 levels and is associated with poorer response to taxane treatment. Our work is the first to demonstrate that the known association between WT1 expression in breast cancer and poor prognosis is potentially due to cancer-related epithelial-to-mesenchymal transition (EMT) and poor chemotherapy response.


TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2.
Tumor necrosis factor-alpha (TNF-α) is a key proinflammatory cytokine. It is generally believed that TNF-α exerts its effects primarily via TNF receptor subtype-1 (TNFR1). We investigated the distinct roles of TNFR1 and TNFR2 in spinal cord synaptic transmission and inflammatory pain. Compared to wild-type (WT) mice, TNFR1- and TNFR2-knockout (KO) mice exhibited normal heat sensitivity and unaltered excitatory synaptic transmission in the spinal cord, as revealed by spontaneous excitatory postsynaptic currents in lamina II neurons of spinal cord slices. However, heat hyperalgesia after intrathecal TNF-α and the second-phase spontaneous pain in the formalin test were reduced in both TNFR1- and TNFR2-KO mice. In particular, heat hyperalgesia after intraplantar injection of complete Freund's adjuvant (CFA) was decreased in the early phase in TNFR2-KO mice but reduced in both the early and later phase in TNFR1-KO mice. Consistently, CFA elicited a transient increase of TNFR2 mRNA levels in the spinal cord on day 1. Notably, TNF-α evoked a drastic increase in spontaneous excitatory postsynaptic current frequency in lamina II neurons, which was abolished in TNFR1-KO mice and reduced in TNFR2-KO mice. TNF-α also increased N-methyl-d-aspartate (NMDA) currents in lamina II neurons, and this increase was abolished in TNFR1-KO mice but retained in TNFR2-KO mice. Finally, intrathecal injection of the NMDA receptor antagonist MK-801 prevented heat hyperalgesia elicited by intrathecal TNF-α. Our findings support a central role of TNF-α in regulating synaptic plasticity (central sensitization) and inflammatory pain via both TNFR1 and TNFR2. Our data also uncover a unique role of TNFR2 in mediating early-phase inflammatory pain. TNF-α is shown to play a critical role in regulating spinal cord synaptic plasticity and central sensitization, and TNFR1 and TNFR2 play a distinct role in regulating different phases of inflammatory pain.


Contribution of Segments to Overall Result in Elite Triathletes: Sprint Distance.
As an alternative to analysing the contribution of performance in specific segments of a triathlon to the overall result as measured in terms of time or position, which has several limitations, previous studies have instead analysed the performance indicator in triathlon. Therefore, the purpose of the study was to analyse the relationship between performance in specific segments and overall performance in terms of sprint distance in elite triathletes through the triathlon performance indicator, instead of using time or position. The official sprint distance results from World Triathlon Series elite events from 2012 to 2019 were examined. In total, 2144 entries were considered, 1143 of which were men and 1001 were women. Performance in the cycling segment presents the best concordance with the overall performance for both elite men (ICCa = 0.871, IC95% = (0.711-0.927)) and elite women (ICCa = 0.907, IC95% = (0.875-0.929)). Although the performance in the running segment does not show the best concordance with the overall performance, the position in this segment does better explain the overall position, especially in elite men and in draft-legal races. These results can support coaches and athletes to identify a specific profile of the strengths and weaknesses of triathletes in competitions, in comparison to their rivals, over a specific distance.


Four Years of Experience Using Problem-Based Learning as a Platform to Develop Student Teaching Skills: A Preliminary Report.
This article was migrated. The article was marked as recommended. Introduction: A graduating medical student should be competent in both teaching and communication skills. This concept is supported by the Accreditation Council for Graduate Medical Education and the Association of American Medical Colleges. Our study describes how we utilized problem-based learning as a platform for developing student teaching skills and to examine preliminary outcomes. Methods: Since 2013, third-year medical students at Florida International University Herbert Wertheim College of Medicine have participated in a mandatory problem-based learning course in parallel to their clinical rotations. During the course orientation students have been led through interactive sessions on writing learning objectives and methods for effective micro-teaching sessions. During seven subsequent sessions, trained faculty members have assessed and provided narrative comments on students' "Ability to Teach Peers" using an anchored developmental scale rubric. Data from four academic years were available for analysis. The Wilcoxon signed-rank test was used to test differences between the initial and final sessions. Results: At the initial session, 39.0% (n=147) received ratings of "mastering." By the final session, 62.6% (n=236) received ratings of "mastering." Conclusion: Our preliminary work demonstrates that a brief orientation to micro-teaching followed by repeated mandatory practice and feedback within our problem-based learning curriculum may serve to build students' teaching skills.


Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD mice by syngeneic splenocytes treated with cytotoxic drugs.
Infusions of syngeneic T-cells, lethally damaged with ultraviolet A light (UVA) and 8-methoxypsoralen (8-MOP), have been reported to prevent or ameliorate a number of autoimmune diseases in humans and in animal models of autoimmune disease. We previously demonstrated that the combination of UVA/8-MOP, or deoxycoformycin and deoxyadenosine (dCF/dAdo), damaged human lymphoid cells by inducing DNA strand breakage and stimulating poly (ADP-ribosyl)ation. These cells subsequently underwent programmed cell death ("apoptosis"). These findings suggested a common mechanism of lymphocyte damage, and that in vitro treatment of T-cells with cCF/dAdo might substitute for UVA/8-MOP. This hypothesis was tested in a model of autoimmune diabetes in the NOD mouse. Young adult female NOD/Wehi mice were given 350 mg/kg cyclophosphamide (CP) on day 1 to induce rapid-onset diabetes and divided into five treatment groups. Four groups received approximately 50 x 10(6) syngeneic mouse splenocytes that had been treated with various cytotoxic agents. 27/40 (68%) of the CP-only control group and 14/30 (48%) of the group given untreated splenocytes developed diabetes. By contrast, only 2/20 (10%) mice of UVA/8-MOP and 3/23 (14%) of dCF/dAdo-treated splenocyte groups developed diabetes (P < 0.01). Diabetes in high spontaneous-diabetes incidence NOD/Lt female mice was also greatly reduced (4/8 untreated vs 1/7 treated; (< 0.05). We postulate that cytotoxic damage to activated splenic T-cells allows their recognition by host T-cells and results in a protective response against autoreactive cells as a form of T-cell vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)


[Effect of the morphological structure of lung cancer on the incidence and type of regional metastases].
A correlation between the frequency, nature of metastatic spreading and histological pattern of lung cancer was established on the basis of a study of 2,107 cases of morphologically confirmed cancer, 1,251 specimens of resected lung tissue and 145 exploratory thoracotomies. Poorly-differentiated cancer of the lung was found to involve frequent formation of metastases at all stages. Metastases generally occur as multiple lesions of lymph nodes.


Management of comorbid insomnia.
Many patients with primary medical or psychiatric disorders may be at risk for the development of comorbid insomnia. Research now suggests that effective treatment and management of the comorbid insomnia may be as important as the primary disorder--especially when the relationship between the two disorders is complex. Advanced practice nurses, in particular nurse practitioners and even professional nurses are well positioned by the nature of their educational preparation to assess for sleep disorders. Insomnia is an insidious illness. It deserves to be properly treated and every individual and patient, no matter their health state, deserves a good night's rest.


Classical capacity of quantum thermal noise channels to within 1.45 bits.
We find a tight upper bound for the classical capacity of quantum thermal noise channels that is within 1/ln2 bits of Holevo's lower bound. This lower bound is achievable using unentangled, classical signal states, namely, displaced coherent states. Thus, we find that while quantum tricks might offer benefits, when it comes to classical communication, they can only help a bit.


[Microbiological diagnosis of sexually transmitted infections (STI): Part 1. Non-viral STI].
Non-viral sexually transmitted infections (STI) are an important cause of physical, psychological and social distress, have severe consequences for women's reproductive health and may be transmitted to the newborn child. These infections are also risk factors for the acquisition and transmission of HIV and other STI, and for premature labor. In the last years we have observed a gradual decrease in the national incidence of gonorrhea. The implementation of a screening program in our country for Chlamydia trachomatis is necessary, since up to 80% of infections in women are asymptomatic. Due to medical, psychosocial and legal reasons, laboratory diagnosis of STI has to be certain. This offers a great challenge to laboratories. Since etiological agents are susceptible to environmental conditions, present a high adaptation to their human host and have particular physiological characteristics, their laboratory diagnosis is more difficult than diagnosis of conventional microorganisms. Otherwise, the diagnostic techniques currently available for non-viral STI are characterized by their excellent sensitivity and specificity, which result of great interest given the curable nature of these infections. Clinical specimens obtained for diagnosis of STI and other genital infections, such as bacterial vaginosis or Candidiasis represent a large proportion of specimens processed by clinical laboratories. Thus, the creation of norms and quality control guidelines for laboratories which diagnose these infections, and also the epidemiologic and genetic surveillance of circulating sex transmitted microorganisms should be considered a priority in our country. The objective of this study is to review current literature on accurate diagnostic procedures especially for three non-viral STI agents: C. trachomatis, N. gonorrhoeae, and Trichomonas vaginalis.


Anti-fibrotic effects of curcumin and some of its analogues in the heart.
Cardiac fibrosis stems from the changes in the expression of fibrotic genes in cardiac fibroblasts (CFs) in response to the tissue damage induced by various cardiovascular diseases (CVDs) leading to their transformation into active myofibroblasts, which produce high amounts of extracellular matrix (ECM) proteins leading, in turn, to excessive deposition of ECM in cardiac tissue. The excessive accumulation of ECM elements causes heart stiffness, tissue scarring, electrical conduction disruption and finally cardiac dysfunction and heart failure. Curcumin (Cur; also known as diferuloylmethane) is a polyphenol compound extracted from rhizomes of Curcuma longa with an influence on an extensive spectrum of biological phenomena including cell proliferation, differentiation, inflammation, pathogenesis, chemoprevention, apoptosis, angiogenesis and cardiac pathological changes. Cumulative evidence has suggested a beneficial role for Cur in improving disrupted cardiac function developed by cardiac fibrosis by establishing a balance between degradation and synthesis of ECM components. There are various molecular mechanisms contributing to the development of cardiac fibrosis. We presented a review of Cur effects on cardiac fibrosis and the discovered underlying mechanisms by them Cur interact to establish its cardio-protective effects.


Nutrition, Immunosenescence, and Infectious Disease: An Overview of the Scientific Evidence on Micronutrients and on Modulation of the Gut Microbiota.
The immune system is key to host defense against pathogenic organisms. Aging is associated with changes in the immune system, with a decline in protective components (immunosenescence), increasing susceptibility to infectious disease, and a chronic elevation in low-grade inflammation (inflammaging), increasing the risk of multiple noncommunicable diseases. Nutrition is a determinant of immune cell function and of the gut microbiota. In turn, the gut microbiota shapes and controls the immune and inflammatory responses. Many older people show changes in the gut microbiota. Age-related changes in immune competence, low-grade inflammation, and gut dysbiosis may be interlinked and may relate, at least in part, to age-related changes in nutrition. A number of micronutrients (vitamins C, D, and E and zinc and selenium) play roles in supporting the function of many immune cell types. Some trials report that providing these micronutrients as individual supplements can reverse immune deficits in older people and/or in those with insufficient intakes. There is inconsistent evidence that this will reduce the risk or severity of infections including respiratory infections. Probiotic, prebiotic, or synbiotic strategies that modulate the gut microbiota, especially by promoting the colonization of lactobacilli and bifidobacteria, have been demonstrated to modulate some immune and inflammatory biomarkers in older people and, in some cases, to reduce the risk and severity of gastrointestinal and respiratory infections, although, again, the evidence is inconsistent. Further research with well-designed and well-powered trials in at-risk older populations is required to be more certain about the role of micronutrients and of strategies that modify the gut microbiota-host relationship in protecting against infection, especially respiratory infection.


Racial (black-white) differences in insulin secretion and clearance in adolescents: the Bogalusa heart study.
Earlier we found black-white contrast in insulin levels in adolescents. The purpose of this study is to assess whether this difference is attributable to alterations in insulin secretion and/or clearance. Fasting circulating insulin and C-peptide concentrations were examined in 1157 adolescents aged 11 to 18 years from a biracial community. Fasting plasma C-peptide, C-peptide to insulin ratio, and glucose to insulin ratio were used as indices of insulin secretion, hepatic insulin clearance, and insulin sensitivity, respectively. After adjusting several covariates (age, sexual maturation, and obesity), black adolescents had higher insulin levels (14.99 vs 12.66 microU/mL in girls). However, they had lower C-peptide levels than their white counterparts, indicating lower insulin secretion by pancreatic beta cells in black adolescents. Moreover, black adolescents had lower levels of C-peptide to insulin ratio than white adolescents (0.14 vs 0.17), suggesting reduced hepatic insulin clearance in black adolescents. In addition, significantly lower levels of glucose to insulin ratio in black girls suggest a reduced insulin sensitivity in this group. Further, differences in insulin levels between white and black girls disappeared after adjusting for differences in C-peptide to insulin ratio. These data suggest that elevated insulin levels observed in black adolescents, especially in black girls, may be attributed to their decreased hepatic insulin clearance, not hypersecretion of insulin.


The biomechanics and function of the secondary restraints to the anterior cruciate ligament.
The primary function of the anterior cruciate ligament has been described as one of restraining anterior motion of the tibia. The passive structures that offer secondary support for the anterior cruciate ligament are the collateral ligaments, the mid-third capsular ligaments, the menisci, and the iliotibial band. In this article, the biomechanics and function of these structures, as well as their effectiveness in providing back-up support for the anterior cruciate ligament, are discussed.


Clinical experience with amrinone in patients with advanced congestive heart failure.
To examine the efficacy of chronic amrinone therapy, the drug was administered to 12 patients with advanced congestive heart failure on average for 27.9 days. The majority of patients had a persistent increase in cardiac index and a persistent decrease in systemic vascular resistance. A decrease in pulmonary arterial diastolic pressure was observed after oral amrinone administration in three patients. However, changes in pulmonary arterial pressure were not consistent in response to intravenous administration of the drug. Thrombocytopenia occurred in four patients, hypogeusia was noted by three patients, and dysosmia developed in two patients. The cumulative survival of the amrinone patients was significantly poorer than that of a second group of patients with congestive heart failure having similar symptoms. These findings indicate that there is a subset of patients with congestive heart failure who do not benefit from chronic amrinone administration and that in such patients its use (especially when given concomitantly with potentially toxic and hypotensive drugs) should be extremely guarded.


East is East … or Is it? Racialization of Asian, Middle Eastern, and Pacific Islander Persons.
The conventional use of racial categories in health research naturalizes "race" in problematic ways that ignore how racial categories function in service of a white-dominated racial hierarchy. In many respects, racial labels are based on geographic designations. For instance, "Asians" are from Asia. Yet, this is not always a tenable proposition. For example, Afghanistan resides in South Asia, and shares a border with China and Pakistan. Yet, people from Afghanistan are not considered Asian, but Middle Eastern, by the US Census. Further, people on the west side of the Island of New Guinea are considered Asian, whereas those on the eastern side are considered Pacific Islander. In this paper, we discuss the complexity of the racial labels related to people originating from Oceania and Asia, and more specifically, those groups commonly referred to as Pacific Islander, Middle Eastern, and Asian. We begin with considerations of the Aggregation Fallacy. Just as the ecological fallacy refers to erroneous inferences about individuals from group data, the aggregation fallacy refers to erroneous inferences about subgroups (e.g., Hmong) from group data (i.e., all Asian Americans), and how these inferences can contribute to stereotypes such as the "model minority." Further, we examine how group averages can be influenced merely by the composition of the subgroups, and how these can in turn be influenced by social policies. We provide a historical overview of some of the issues facing Pacific Islander, Middle Eastern, and Asian communities, and conclude with directions for future research.


Evaluation of styrene-divinylbenzene beads as a support to immobilize lipases.
A commercial and very hydrophobic styrene-divinylbenzene matrix, MCI GEL® CHP20P, has been compared to octyl-Sepharose® beads as support to immobilize three different enzymes: lipases from Thermomyces lanuginosus (TLL) and from Rhizomucor miehie (RML) and Lecitase® Ultra, a commercial artificial phospholipase. The immobilization mechanism on both supports was similar: interfacial activation of the enzymes versus the hydrophobic surface of the supports. Immobilization rate and loading capacity is much higher using MCI GEL® CHP20P compared to octyl-Sepharose® (87.2 mg protein/g of support using TLL, 310 mg/g using RML and 180 mg/g using Lecitase® Ultra). The thermal stability of all new preparations is much lower than that of the standard octyl-Sepharose® immobilized preparations, while the opposite occurs when the inactivations were performed in the presence of organic co-solvents. Regarding the hydrolytic activities, the results were strongly dependent on the substrate and pH of measurement. Octyl-Sepharose® immobilized enzymes were more active versus p-NPB than the enzymes immobilized on MCI GEL® CHP20P, while RML became 700-fold less active versus methyl phenylacetate. Thus, the immobilization of a lipase on this matrix needs to be empirically evaluated, since it may present very positive effects in some cases while in other cases it may have very negative ones.


Sirolimus and mycophenolate mofetil after liver transplantation.
Since the approval of sirolimus (SRL) as an immunosuppressive agent in renal transplantation, several liver transplant centres have introduced this agent to the immunosuppression regimen. We present here a retrospective follow-up study of late conversion to sirolimus and mycophenolate mofetil (MMF) as immunosuppressive agents after liver transplantation (LTX). From July 2001 to March 2002, seven liver transplant recipients (three female, 59 (41-66) years old) were enrolled in this study. Indications for liver transplantation were hepatitis B and/or hepatitis C (three), alcohol-induced cirrhosis (three) and Wilson's syndrome (hepatolenticular degeneration) (one). LTX was performed by standard (four) or piggy-back (three) technique. The switch to SRL was performed 62 (37-118) months after LTX; the reasons for the switch from cyclosporine or tacrolimus to SRL were renal (six) or neurological (one) impairment. As immunosuppressive therapy, SRL at trough levels of 4-10 ng/ml and MMF at trough levels of approximately 1 micro g/ml were administered. Mean follow-up time under SRL per patient was 137 (26-258 days). Patient and graft survival was 100% during SRL therapy, and there were neither rejection episodes nor infections. Renal function improved in five of the six patients (83.3%) whom we had switched to SRL due to renal impairment. In the patient whom we switched to SRL due to neurological impairment, the neurological symptoms abated, and renal function improved. Side effects (hypertriglyceridaemia, hypercholesterolaemia, exanthema) became manifest in three patients (42.8%). Cessation of therapy due to side effects was necessary in two patients (exanthema: one, hypertriglyceridaemia: one). One patient refused to continue the therapy with SRL because he wanted tablets, and we only had SRL in fluid form. The data of our study suggest that SRL is a potent immunosuppressive agent of potential benefit in clinical LTX. SRL in combination with MMF provided sufficient immunosuppression of liver allografts in the late course after LTX. Side effects were reversible with dose reduction or cessation of therapy. We can thus conclude that SRL might offer an immunosuppressive therapy for patients with renal or neurological impairment after LTX.


A simple bioanalytical method for the quantification of antiepileptic drugs in dried blood spots.
An increasing number of publications on the dried blood spot (DBS) sampling approach for the quantification of drugs and metabolites have been spurred on by the inherent advantages of this sampling technique. In the present research, a selective and sensitive high-performance liquid chromatography method for the concurrent determination of multiple antiepileptic drugs (AEDs) [levetiracetam (LVT), lamotrigine (LTG), phenobarbital (PHB)], carbamazepine (CBZ) and its active metabolite carbamazepine-10,11 epoxide (CBZE)] in a single DBS has been developed and validated. Whole blood was spotted onto Guthrie cards and dried. Using a standard punch (6mm diameter), a circular disc was punched from the card and extracted with methanol: acetonitrile (3:1, v/v) containing hexobarbital (Internal Standard) and sonicated prior to evaporation. The extract was then dissolved in water and vortex mixed before undergoing solid phase extraction using HLB cartridges. Chromatographic separation of the AEDs was achieved using Waters XBridge™ C18 column with a gradient system. The developed method was linear over the concentration ranges studied with r≥0.995 for all compounds. The lower limits of quantification (LLOQs) were 2, 1, 2, 0.5 and 1 μg/mL for LVT, LTG, PHB, CBZE and CBZ, respectively. Accuracy (%RE) and precision (%CV) values for within and between day were <20% at the LLOQs and <15% at all other concentrations tested. This method was successfully applied to the analysis of the AEDs in DBS samples taken from children with epilepsy for the assessment of their adherence to prescribed treatments.


Identification of Patients At-Risk of QT Interval Prolongation during Medication Reviews: A Missed Opportunity?
The prolongation of the QT interval is a relatively rare but serious adverse drug reaction. It can lead to torsade de pointes, which is potentially life-threatening. The study's objectives were: determine the use of QT interval-prolonging drugs in an elderly community-dwelling population at risk of medication misadventure and identify recommendations regarding the risk of QT interval prolongation made by pharmacists when performing medication reviews. In a retrospective evaluation, 500 medication review reports from Australian pharmacists were analysed. In patients taking at least one QT interval-prolonging drug, the individual risk of drug-induced QT interval prolongation was assessed. Recommendations of pharmacists to avoid the occurrence of this drug-related problem were examined. There was a high prevalence of use of potentially QT interval-prolonging drugs (71% patients), with 11% of patients taking at least one drug with a known risk. Pharmacists provided specific recommendations in only eight out of 35 patients (23%) with a high-risk score and taking drugs with known risk of QT interval prolongation. Pharmacists' recommendations, when present, were focused on drugs with known risk of QT interval prolongation, rather than patients' additional risk factors. There is a need to improve knowledge and awareness of this topic among pharmacists performing medication reviews.


Numerical-Experimental Analysis toward the Strain Rate Sensitivity of 3D-Printed Nylon Reinforced by Short Carbon Fiber.
Despite the application of the Additive Manufacturing process and the ability of parts' construction directly from a 3D model, particular attention should be taken into account to improve their mechanical characteristics. In this paper, we present the effect of individual process variables and the strain-rate sensitivity of Onyx (Nylon mixed with chopped carbon fiber) manufactured by Fused Filament Fabrication (FFF), using both experimental and simulation manners. The main objective of this paper is to present the effect of the selected printing parameters (print speed and platform temperature) and the sensitivity of the 3D-printed specimen to the strain rate during tensile behavior. A strong variation of tensile behavior for each set of conditions has been observed during the quasi-static tensile test. The variation of 40 °C in the platform temperature results in a 10% and 11% increase in Young's modulus and tensile strength, and 8% decrease in the failure strain, respectively. The variation of 20 mm·s-1 in print speed results in a 14% increase in the tensile strength and 11% decrease in the failure strain. The individual effect of process variables is inevitable and affects the mechanical behavior of the 3D-printed composite, as observed from the SEM micrographs (ductile to brittle fracture). The best condition according to their tensile behavior was chosen to investigate the strain rate sensitivity of the printed specimens both experimentally and using Finite Element (FE) simulations. As observed, the strain rate clearly affects the failure mechanism and the predicted behavior using the FE simulation. Increase in the elongation speed from 1 mm·min-1 to 100 mm·min-1, results in a considerable increase in Young's modulus. SEM micrographs demonstrated that although the mechanical behavior of the material varied by increasing the strain rate, the failure mechanism altered from ductile to brittle failure.


Unequivocal identification of subpopulations in putative multiclonal Trypanosoma cruzi strains by FACs single cell sorting and genotyping.
Trypanosoma cruzi, the etiological agent of Chagas disease, is a polymorphic species. Evidence suggests that the majority of the T. cruzi populations isolated from afflicted humans, reservoir animals, or vectors are multiclonal. However, the extent and the complexity of multiclonality remain to be established, since aneuploidy cannot be excluded and current conventional cloning methods cannot identify all the representative clones in an infection. To answer this question, we adapted a methodology originally described for analyzing single spermatozoids, to isolate and study single T. cruzi parasites. Accordingly, the cloning apparatus of a Fluorescence-Activated Cell Sorter (FACS) was used to sort single T. cruzi cells directly into 96-wells microplates. Cells were then genotyped using two polymorphic genomic markers and four microsatellite loci. We validated this methodology by testing four T. cruzi populations: one control artificial mixture composed of two monoclonal populations--Silvio X10 cl1 (TcI) and Esmeraldo cl3 (TcII)--and three naturally occurring strains, one isolated from a vector (A316A R7) and two others derived from the first reported human case of Chagas disease. Using this innovative approach, we were able to successfully describe the whole complexity of these natural strains, revealing their multiclonal status. In addition, our results demonstrate that these T. cruzi populations are formed of more clones than originally expected. The method also permitted estimating of the proportion of each subpopulation of the tested strains. The single-cell genotyping approach allowed analysis of intrapopulation diversity at a level of detail not achieved previously, and may thus improve our comprehension of population structure and dynamics of T. cruzi. Finally, this methodology is capable to settle once and for all controversies on the issue of multiclonality.


Microfluidic Fabrication of Monodisperse and Recyclable TiO2-Poly(ethylene glycol) Diacrylate Hybrid Microgels for Removal of Methylene Blue from Aqueous Medium.
Nearly monodisperse titanium oxide-polyethylene glycol diacrylate [TiO2-P(EGDA)] hybrid microbeads containing 0.5 wt % TiO2 nanoparticles entrapped within a P(EGDA) cross-linked polymeric network were synthesized using a modular Lego-inspired glass capillary microfluidic device. TiO2-P(EGDA) hybrid microgels were characterized by optical microscopy, scanning electron microscopy, X-ray diffraction, energy dispersive X-ray spectroscopy, and thermogravimetric analysis. The fabricated TiO2-P(EGDA) hybrid microgel system showed 100% removal efficiency of methylene blue (MB) from its 1-3 ppm aqueous solutions after 4 h of UV light irradiation at 0.2 mW/cm2 at the loading of 25 g/L photocatalyst beads in the reaction mixture, corresponding to the loading of naked TiO2 of just 0.025 g/L. No decrease in photocatalytic efficiency was observed in 10 repeated runs with recycled photocatalyst using a fresh 1 ppm MB solution in each cycle. The rate of photocatalytic degradation was controlled by the UV light irradiance, catalyst loading, and the initial dye concentration. Physical adsorption of MB onto the surface of composite microgel was also observed. The adsorption data was best fitted with the Langmuir adsorption isotherm and the Elovich kinetic model. TiO2-P(EGDA) microgel beads are biocompatible, can be prepared with a tunable size in the microfluidic device, and can easily be separated from the reaction mixture by gravity settling. The TiO2-P(EGDA) system can be used for the removal of other toxic dyes and micropollutants from industrial wastewater.


Identity and dating commitment among women and men in college.
Lower division and upper division college women's and men's commitment in a dating relationship was examined in connection with their (a) gender role attitudes, (b) educational aspirations, (c) certainty about their future vocation, and (d) the importance they attach to work vs. marriage as a source of life satisfaction. Dating commitment was also examined for women in relation to their dedication to work for pay after marriage, and for men in terms of their ideas about their future wife working. The more certain upper division college women's vocational identity, the more committed they were to their dating partner, but the more they planned to work after marriage the less involved they were in a relationship. Additionally, upper division women who placed more importance on a job than marriage and who had a clearer vocational identity were less involved in a relationship. The clearer upper division men's vocational identity, the more committed they were in a relationship. Lower division men who placed more importance on work compared to marriage were less involved in a dating relationship. The results are discussed in light of Erikson's stages of identity development and more recent research that suggests women's identity development follows a different course from men's.


Psychological effects of chemical weapons: a follow-up study of First World War veterans.
Chemical weapons exercise an enduring and often powerful psychological effect. This had been recognized during the First World War when it was shown that the symptoms of stress mimicked those of mild exposure to gas. Debate about long-term effects followed the suggestion that gassing triggered latent tuberculosis. A random sample of 103 First World War servicemen awarded a war pension for the effects of gas, but without evidence of chronic respiratory pathology, were subjected to cluster analysis using 25 common symptoms. The consistency of symptom reporting was also investigated across repeated follow-ups. Cluster analysis identified four groups: one (n=56) with a range of somatic symptoms, a second (n=30) with a focus on the respiratory system, a third (n=12) with a predominance of neuropsychiatric symptoms, and a fourth (n=5) with a narrow band of symptoms related to the throat and breathing difficulties. Veterans from the neuropsychiatric cluster had multiple diagnoses including neurasthenia and disordered action of the heart, and reported many more symptoms than those in the three somatic clusters. Mild or intermittent respiratory disorders in the post-war period supported beliefs about the damaging effects of gas in the three somatic clusters. By contrast, the neuropsychiatric group did not report new respiratory illnesses. For this cluster, the experience of gassing in a context of extreme danger may have been responsible for the intensity of their symptoms, which showed no sign of diminution over the 12-year follow-up.


Rock with me: the role of movement synchrony in infants' social and nonsocial choices.
Matching the timing of one's movements to the movements of others has been proposed to increase affiliation and prosociality. Although coordinated movements facilitate early social interactions, not much is known about the mechanisms and effects of movement synchrony throughout development. Two studies investigated 12-month-olds' (Study 1, N = 40) and 9-month-olds' (Study 2, N = 41) preferences for synchronous others in a social as opposed to a nonsocial context. It was found that movement synchrony exclusively guides infants' social choices at 12 months. In contrast, 9-month-olds did not show any preferences for synchronous movements in social or nonsocial contexts. Results suggest that movement synchrony is important in guiding infants' social preferences and its effects emerge toward the end of the 1st year of life.


Risk Stratification in Pediatric Acute Respiratory Distress Syndrome: A Multicenter Observational Study.
The Pediatric Acute Lung Injury Consensus Conference developed a pediatric specific definition for acute respiratory distress syndrome (PARDS). In this definition, severity of lung disease is stratified into mild, moderate, and severe groups. We aim to describe the epidemiology of patients with PARDS across Asia and evaluate whether the Pediatric Acute Lung Injury Consensus Conference risk stratification accurately predicts outcome in PARDS. A multicenter, retrospective, descriptive cohort study. Ten multidisciplinary PICUs in Asia. All mechanically ventilated children meeting the Pediatric Acute Lung Injury Consensus Conference criteria for PARDS between 2009 and 2015. None. Data on epidemiology, ventilation, adjunct therapies, and clinical outcomes were collected. Patients were followed for 100 days post diagnosis of PARDS. A total of 373 patients were included. There were 89 (23.9%), 149 (39.9%), and 135 (36.2%) patients with mild, moderate, and severe PARDS, respectively. The most common risk factor for PARDS was pneumonia/lower respiratory tract infection (309 [82.8%]). Higher category of severity of PARDS was associated with lower ventilator-free days (22 [17-25], 16 [0-23], 6 [0-19]; p < 0.001 for mild, moderate, and severe, respectively) and PICU free days (19 [11-24], 15 [0-22], 5 [0-20]; p < 0.001 for mild, moderate, and severe, respectively). Overall PICU mortality for PARDS was 113 of 373 (30.3%), and 100-day mortality was 126 of 317 (39.7%). After adjusting for site, presence of comorbidities and severity of illness in the multivariate Cox proportional hazard regression model, patients with moderate (hazard ratio, 1.88 [95% CI, 1.03-3.45]; p = 0.039) and severe PARDS (hazard ratio, 3.18 [95% CI, 1.68, 6.02]; p < 0.001) had higher risk of mortality compared with those with mild PARDS. Mortality from PARDS is high in Asia. The Pediatric Acute Lung Injury Consensus Conference definition of PARDS is a useful tool for risk stratification.


Cardiovascular involvement in celiac disease.
Celiac disease (CD) is an autoimmune response to ingestion of gluten protein, which is found in wheat, rye, and barley grains, and results in both small intestinal manifestations, including villous atrophy, as well as systemic manifestations. The main treatment for the disease is a gluten-free diet (GFD), which typically results in the restoration of the small intestinal villi, and restoration of other affected organ systems, to their normal functioning. In an increasing number of recently published studies, there has been great interest in the occurrence of alterations in the cardiovascular system in untreated CD. Herein, published studies in which CD and cardiovascular terms appear in the title of the study were reviewed. The publications were categorized into one of several types: (1) articles (including cohort and case-control studies); (2) reviews and meta-analyses; (3) case studies (one to three patient reports); (4) letters; (5) editorials; and (6) abstracts (used when no full-length work had been published). The studies were subdivided as either heart or vascular studies, and were further characterized by the particular condition that was evident in conjunction with CD. Publication information was determined using the Google Scholar search tool. For each publication, its type and year of publication were tabulated. Salient information from each article was then compiled. It was determined that there has been a sharp increase in the number of CD - cardiovascular studies since 2000. Most of the publications are either of the type "article" or "case study". The largest number of documents published concerned CD in conjunction with cardiomyopathy (33 studies), and there have also been substantial numbers of studies published on CD and thrombosis (27), cardiovascular risk (17), atherosclerosis (13), stroke (12), arterial function (11), and ischemic heart disease (11). Based on the published research, it can be concluded that many types of cardiovascular issues can occur in untreated CD patients, but that most tend to resolve on a GFD, often in conjunction with the healing of small intestinal villous atrophy. However, in some cases the alterations are irreversible, underscoring the need for CD screening and treatment when cardiovascular issues arise of unknown etiology.


A new organ preservation solution for static cold storage of the liver. Amniotic fluid.
To evaluate the effect of amniotic fluid in liver preservation in organ transplantation, and compare it with standard preservation solutions. The groups consisted of Group 1: Ringer Lactate (RL) group, Group 2: HTK group, Group 3: UW group, Group 4: AF group. The livers of rats from Group 1, 2, 3, and 4 were perfused and placed into falcon tubes containing RL, HTK, UW, and AF solutions at +4°C, respectively. The tubes were stored for 12 hours in the refrigerator at +4°C. Tissue samples were taken at the 6th and 12th hours for histopathological examinations of the perfused livers, and storage solutions for biochemical analyzes at 6th and 12th hours. AF was shown to maintain organ viability by reducing the number of cells undergoing apoptosis. Histopathological changes such as sinusoidal dilatation, hydropic degeneration, and focal necrosis were found to be similar to the groups in which the standard organ preservation solutions were used. Additionally, the results of INOS, IL-10, and TNF-α,which were evaluated immunohistochemically, have been shown to be similar to the UW and HTK groups. AF provided conservation similar to UW and HTK in the 12-hour liver SCS process. The fact that apoptosis values are comparable to standard preservation solutions supports the success of AF in the cold storage of the liver.


The Diagnostic Yield of Malignancy Comparing Cytology, FISH, and Molecular Analysis of Cell Free Cytology Brush Supernatant in Patients With Biliary Strictures Undergoing Endoscopic Retrograde Cholangiography (ERC): A Prospective Study.
Routine cytology of biliary stricture brushings obtained during endoscopic retrograde cholangiopancreatography (ERCP) has suboptimal sensitivity for malignancy. We compared the individual and combined ability of cytology, fluorescence in situ hybridization (FISH) analysis and PCR-based mutation profiling (MP) to detect malignancy in standard biliary brushings. We performed a prospective study of patients undergoing ERCP using histology or 1 year follow-up to determine patient outcomes. MP was performed on free-DNA from biliary brushing specimens using normally discarded supernatant fluid. MP examined KRAS point mutations and tumor suppressor gene associated loss of heterozygosity mutations at 10 genomic loci. FISH examined chromosome specific gains or losses. A total of 101 patients were included in final analysis and 69% had malignancy. Cytology had 26% sensitivity and 100% specificity for malignancy. Using either FISH or MP in combination with cytology increased sensitivity to 44% and 56%, respectively. The combination of all 3 tests (cytology, FISH, and MP) had the highest sensitivity for malignancy (66%). There was no difference in the specificity of cytology, FISH or MP testing when examined alone or in combination. MP improved diagnostic yield of each procedure from 22% to 100%; FISH improved yield to 90%. MP detected 21 malignancies beyond that identified by cytology; FISH detected an additional 13. The combination of FISH and MP testing detected an additional 28 malignancies. Both MP and FISH are complimentary molecular tests that can significantly increase detection of biliary malignancies when used in combination with routine cytology of standard biliary brush specimens.


Effect of prohydrojasmon on total phenolic content, anthocyanin accumulation and antioxidant activity in komatsuna and lettuce.
Prohydrojasmon has been reported to improve the quality of crops. However, most previous studies have investigated its application on fruits. Here, we evaluated the effect of prohydrojasmon on the growth and total phenolic content, anthocyanin content, and antioxidant activity in komatsuna (Brassica rapa var. periviridis) and lettuce (Lactuca sativa L.). Prohydrojasmon did not show any serious inhibitory effect. Prohydrojasmon applied to komatsuna at a concentration of 0.5 µM significantly increased the total phenolic content and anthocyanin content, and a concentration of 1 µM increased the antioxidant activity. In lettuce, prohydrojasmon at a concentration of 400 µM significantly increased the total phenolic content and anthocyanin content, while a concentration of 0.5 µM significantly increased the antioxidant activity. These results suggest that prohydrojasmon positively affects the phenolic compound and anthocyanin accumulation and antioxidant activity in komatsuna and lettuce without adversely affecting growth.


[Intra-orbital dacryops. Report of a case].
We report a case of intra-orbital Dacryops in a 7-year-old child. The presenting sign was progressive exophtalmus. The patient was operated via a lateral approach allowing total removal of the cyst without recurrence after one year. The clinical, radiological (CT Scan and MRI) and therapeutical aspects are discussed.


Textilinins from Pseudonaja textilis textilis. Characterization of two plasmin inhibitors that reduce bleeding in an animal model.
The incidence of vein-graft occlusion associated with myocardial infarction and thrombosis following the use of the plasmin inhibitor, aprotinin, to reduce blood loss during vascular surgery has prompted the isolation of an alternative kinetically distinct inhibitor of plasmin from the venom of Pseudonaja textilis. This inhibitor has been called textilinin (Txln) and two distinct forms have been isolated from the Brown-snake venom (molecular weight, 6688 and 6692). A comparison of plasmin inhibitor constants for aprotinin and the Txlns 1 and 2 indicated that the former bound very tightly (inhibitor constant, Ki approximately 10(-11) mol/l), while both of the latter bound less tightly (Ki approximately 10(-9) mol/l). Homogeneity of Txlns 1 and 2 was confirmed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and mass spectrometry. A sequence difference of six amino acids was observed between the two forms of Txln. Txln 1 and 2 showed, respectively, 45 and 43% homology with aprotinin, while there was 58 and 55% homology, respectively, with a plasmin inhibitor from the venom of eastern Taipan, Oxyuranus scutellatus. Both Txlns have six cysteines, like other inhibitors of this group, and homology was determined by alignment of these cysteines. Both have been shown to reduce blood loss by about 60% in a murine tail vein bleeding model. It is proposed that the kinetic profiles of Txln 1 and 2 for plasmin allow the arrest of haemorrhage without the possible threat of thrombosis.


Evaluating methods for Avian avulavirus-1 whole genome sequencing.
Avian avulavirus-1 (AAvV-1, previously Newcastle Disease Virus) is responsible for poultry and wild birds' disease outbreaks. Numerous whole genome sequencing methods were reported for this virus. These methods included cloning, specific primers amplification, shotgun PCR approaches, Sequence Independent Single Primer Amplification and next generation sequencing platform kits. Three methods were used to sequence 173 Israeli Avian avulavirus-1 field isolates and one vaccine strain (VH). The sequencing was performed on Proton and Ion Torrent Personal Genome Machine and to a lesser extent, Illumina MiSeq and NextSeq sequencers. Target specific primers (SP) and Sequence Independent Single Primer Amplification (SISPA) products sequenced via the Ion torrent sequencer had a high error rate and truncated genomes. All the next generation sequencing platform sequencing kits generated high sequence accuracy and near-complete genomic size. A high level of mutations was observed in the intergenic regions between the avian avulavirus-1 genes. Within genes, multiple regions are more mutated than the Fusion region currently used for typing. Our findings suggest that the whole genome sequencing by the Ion torrent sequencing kit is sufficient. However, when higher fidelity is desired, the Illumina NextSeq and Proton torrent sequencing kits were found to be preferable.


Macromolecular organization and genetic mapping of a rapidly evolving chromosome-specific tandem repeat family (B77) in cotton (Gossypium).
Isolation and characterization of the most prominent repetitive element families in the genome of tetraploid cotton (Gossypium barbadense L; [39]) revealed a small subset of families that showed very different properties in tetraploids than in their diploid progenitors, separated by 1-2 million years. One element, B77, was characterized in detail, and compared to the well-conserved 5S and 45S rRNA genes. The 572 bp B77 repeat was found to be concentrated in several discontinuous tandem arrays confined to a single 550 kb SalI fragment in tetraploid cotton. Genetic mapping based on the absence of the pentameric 'rung' in the G. barbadense 'ladder' showed that B77 maps to a D-subgenome chromosome. In situ hybridization supports the contention that the array is confined largely to a single chromosomal site in the D-subgenome. The B77 repeat has undergone a substantial increase in copy number since formation of tetraploid cotton from its diploid relatives. RFLPs observed among tetraploid cotton species suggest that amplification and/or rearrangement of the repeat may have continued after divergence of the five tetraploid cotton species. B77 contains many short direct repeats and shares significant DNA sequence homology with a Nicotiana alata retrotransposon Tna1-2 integrase motif. The recent amplification of B77 on linkage group D04 suggests that the D-subgenome of tetraploid cotton may be subject to different evolutionary constraints than the D-genome diploid chromosomes, which exhibit few genome-specific elements. Further, the abundance of B77 in G. gossypioides supports independent evidence that it may be the closest extant relative of the D-genome ancestor of cotton.


Intranasal delivery of mesenchymal stem cells-derived extracellular vesicles for the treatment of neurological diseases.
Neurological disorders are diseases of the central nervous system (CNS), characterized by a progressive degeneration of cells and deficiencies in neural functions. Mesenchymal stem cells (MSCs) are a promising therapy for diseases and disorders of the CNS. Increasing evidence suggests that their beneficial abilities can be attributed to their paracrine secretion of extracellular vesicles (EVs). Administration of EVs that contain a mixture of proteins, lipids, and nucleic acids, resembling the secretome of MSCs, has been shown to mimic most of the effects of the parental cells. Moreover, the small size and safety profile of EVs provide a number of advantages over cell transplantation. Intranasal (IN) administration of EVs has been established as an effective and reliable way to bypass the blood-brain barrier and deliver drugs to the CNS. In addition to pharmacological drugs, EVs can be loaded with a diverse range of cargo designed to modulate gene expression and protein functions in recipient cells, and lead to immunomodulation, neurogenesis, neuroprotection, and degradation of protein aggregates. In this review, we will explore the proposed physiological pathways by which EVs migrate through the nasal route to the CNS where they can actively target a region of injury or inflammation and exert their therapeutic effects. We will summarize the functional outcomes observed in animal models of neurological diseases following IN treatment with MSC-derived EVs. We will also examine key mechanisms that have been suggested to mediate the beneficial effects of EV-based therapy.


The impact of age and race on longevity in pediatric astrocytic tumors: A population-based study.
Despite improvements in pediatric brain tumor outcomes, the survivors of childhood brain tumor are burdened by multiple comorbidities. This work reports on the relative survival ratios and excess mortality rate in children with astrocytic tumors over the past four decades. Survival analysis was conducted using flexible parametric model to estimate relative survival and excess mortality rate for non-white and white children (0-19 years old) using the Surveillance, Epidemiology & End Results (SEER) database. We incorporated age group and year of diagnosis into the model to estimate these indices for the period of 1973-2010. Progressive decline in relative survival ratios was noted over time. Non-white children had lower survival rates than white children, and these survival patterns persisted over the four-decade span of the study. Fifty percent of non-white survivors were deceased 30 years post diagnosis, compared to 35 years in white survivors. Survivors of childhood brain tumors have progressively lower survival rates as they get older, and this is higher in non-white when compared to white children. Future research efforts need to focus on understanding the factors mediating the effect of the tumor or its treatment on survival in these patients, and the ethnic variations that derive these survival trends.


Effects of portal infusion of hypertonic solution on jejunal electrolyte transport in anesthetized dogs.
Jejunal electrolyte absorption was measured in the jejunal loops of anesthetized dogs during infusions of hypertonic solutions via the portal vein. The net Na absorption was not influenced by the 9% NaCl infusion into the inferior vena cava, although it was significantly attenuated by the portal 9% NaCl infusion. This effect may not be due to the osmotic stimulus, since the portal 50% glucose or 6.5% LiCl infusion had no significant influence on the net Na absorption. To determine the mechanism of the decrease in the net Na absorption during the portal hypertonic NaCl infusion, the net Na absorption was measured after the section of anterior and posterior hepatic nerves (SAPH) or intravenous atropine injection. Both SAPH and the intravenous atropine injection completely blocked the effect of the portal 9% NaCl infusion on the net Na absorption. These results indicate that 1) net Na absorption in dog jejunum is depressed by the hypertonic NaCl infusion via the portal vein; 2) the effect is NaCl specific and may not be due to the osmotic stimulus; and 3) the afferent limbs of this effect are the anterior and posterior hepatic nerves, and the efferent limb of this effect is the vagus nerve. Thus the hepatojejunal reflex may play an important role in the regulation of body fluid homeostasis.


Selective Molecular Separation on Ti3C2Tx-Graphene Oxide Membranes during Pressure-Driven Filtration: Comparison with Graphene Oxide and MXenes.
In this work, we prepared 90 nm thick Ti3C2Tx-graphene oxide (GO) membranes laminated on a porous support by mixing GO with Ti3C2Tx. This process was chosen to prevent the penetration of target molecules through inter-edge defects or voids with poor packing. The lattice period of the prepared membrane was 14.28 Å, as being swelled with water, resulting in an effective interlayer spacing of around 5 Å, which corresponds to two layers of water molecules. The composite membranes effectively rejected dye molecules with hydrated radii above 5 Å, as well as positively charged dye molecules, during pressure-driven filtration at 5 bar. Rejection rates were 68% for methyl red, 99.5% for methylene blue, 93.5% for rose Bengal, and 100% for brilliant blue (hydrated radii of 4.87, 5.04, 5.88, and 7.98 Å, respectively). Additionally, the rejections of composite membrane were compared with GO membrane and Ti3C2Tx membrane.


Differential Effects of Maternal Yolk Androgens on Male and Female Offspring: A Role for Sex-Specific Selection?
Maternal hormones are important mediators of prenatal maternal effects in animals. Although their effects on offspring phenotype are often sex-specific, the reason why sometimes sons are more sensitive to prenatal hormone exposure and sometimes daughters is not well understood. Here I combine an experimental manipulation of yolk testosterone concentration in the egg and quantification of selection acting on yolk androgen-sensitive traits in a natural population of great tits (Parus major) with a literature review to test the hypothesis that sex-specific selection on traits affected by yolk androgens determines which sex is more sensitive to prenatal hormone exposure. An experimental increase of the testosterone content in the egg boosted the post-hatching growth of male, but not female great tit nestlings. However, I found no evidence that survival selection on body mass or size is acting differently in the two sexes. A literature review revealed that yolk androgen manipulations affect the growth of males and females differently across species. Interestingly, in studies performed in the wild a significant association between the strength and direction of sexual size dimorphism and sex-specific sensitivities to yolk androgens was observed. In studies performed in captivity, no such relationship was found. Thus, across species there is some evidence that sex-specific selection on body size influences how strongly growth trajectories of males and females are affected by maternally-derived yolk androgens.


A Step in the Right Direction: Evaluating the Effectiveness of Customized Stepping Game Software and Balance Boards for Balance Rehabilitation Therapy and Measurement.
The incidence of falls significantly increases with age in older populations. Traditionally, exercise interventions have been effective in improving balance and strength, thereby reducing the number and risk of falls. To minimize costs, to make exercise more engaging, and to reduce the burden on therapists, the use of serious gaming using virtual reality technologies has become more common. These gaming systems allow the evaluation of compensatory strategies to reduce falls. One of the easiest compensatory strategies to reduce falls is to step forward. To evaluate stepping, the time it takes to step, response times, and reaction times, a stepping game was developed using two Nintendo Wii Balance Boards™.The objective of this study was to investigate the stepping game system for its efficacy as a supplemental balance therapy by evaluating functional outcomes and participant satisfaction. The game was able to identify changes in performance measures (response time, reaction time and step time) for some participants over the span of the exercise program; however, a larger sample size and a stricter protocol is necessary to evaluate the clinical significance.Clinical Relevance- The stepping game appears to be more sensitive to detecting change in balance related measures including step time, reaction time, response time, than the Berg Balance Scale.


Association between foot thermal responses and shear forces during turning gait in young adults.
The human foot typically changes temperature between pre and post-locomotion activities. However, the mechanisms responsible for temperature changes within the foot are currently unclear. Prior studies indicate that shear forces may increase foot temperature during locomotion. Here, we examined the shear-temperature relationship using turning gait with varying radii to manipulate magnitudes of shear onto the foot. Healthy adult participants (N = 18) walked barefoot on their toes for 5 minutes at a speed of 1.0 m s-1 at three different radii (1.0, 1.5, and 2.0 m). Toe-walking was utilized so that a standard force plate could measure shear localized to the forefoot. A thermal imaging camera was used to quantify the temperature changes from pre to post toe-walking (ΔT), including the entire foot and forefoot regions on the external limb (limb farther from the center of the curved path) and internal limb. We found that shear impulse was positively associated with ΔT within the entire foot (P < 0.001) and forefoot (P < 0.001): specifically, for every unit increase in shear, the temperature of the entire foot and forefoot increased by 0.11 and 0.17 °C, respectively. While ΔT, on average, decreased following the toe-walking trials (i.e., became colder), a significant change in ΔT was observed between radii conditions and between external versus internal limbs. In particular, ΔT was greater (i.e., less negative) when walking at smaller radii (P < 0.01) and was greater on the external limb (P < 0.01) in both the entire foot and forefoot regions, which were likely explained by greater shear forces with smaller radii (P < 0.0001) and on the external limb (P < 0.0001). Altogether, our results support the relationship between shear and foot temperature responses. These findings may motivate studying turning gait in the future to quantify the relationship between shear and foot temperature in individuals who are susceptible to abnormal thermoregulation.


Clinical transformation: the key to green nephrology.
Climate change represents a major global public health threat. The very provision of healthcare itself has a significant untoward effect on the environment, to which kidney care is likely to contribute disproportionately. In this article we describe the four principles we believe will underpin a successful transformation to lower carbon kidney care: disease prevention, patient empowerment, lean service delivery and the preferential use of low-carbon technologies. We illustrate their application and their co-benefits, such as improvements in patient care and reductions in cost, with examples.


Is there a role for warfarin anymore?
Reduction of atrial fibrillation-associated stroke risk has become the leading indication for warfarin use. Optimal management of warfarin can only be achieved with a relatively complex infrastructure. Alternative anticoagulant agents have been developed, and 3 have demonstrated effectiveness, safety, and adherence that are comparable or superior to warfarin in the clinical trial setting. None of the novel agents requires routine laboratory testing to demonstrate effective anticoagulation. Whereas these new agents present potential advantages, such as fixed dosing and dramatically reduced intracranial hemorrhaging, they are also subject to caveats that ought to be considered in the context of an "ideal" anticoagulant. If used casually, they have the potential to worsen rather than improve health care outcomes. There is little question that the management burden of the novel agents will be less than with warfarin. However, with a hemorrhagic risk that was similar to warfarin in these trials, there will likely remain a significant need for both baseline education and some level of focused interval follow-up to assess for bleeding risk and adherence considerations. These novel agents offer a definite advance in the available management options for thromboembolic disease, but until we understand the requirements for safe and effective use in the routine clinical setting, we will not be able to establish the extent to which they should replace warfarin.


Fat-to-muscle Ratio: A New Indicator for Coronary Artery Disease in Healthy Adults.
Background: Coronary artery disease (CAD) is an important issue in public health. Previous studies have shown that the ratio of fat to muscle mass is a significant predictor of metabolic disease, and it is known to be associated with atherosclerosis. In this study, we evaluated the association between the fat-to-muscle ratio (FMR) and CAD in healthy adults. Methods: A total of 617 participants without diabetes mellitus, hypertension, known CAD, or stroke who visited the Health Promotion Center from 2009 to 2018 were included in this study. Computed tomography imaging and bioelectrical impedance analysis were used to ascertain the coronary artery calcium (CAC) score, degree of CAD, and FMR. Results: Univariate logistic regression analysis showed that old age, male sex, smoking history, creatinine, aspartate aminotransferase, gamma-glutamyl transferase, uric acid, total cholesterol, and low-density lipoprotein cholesterol were significantly associated with CAC. After adjusting for potential confounding covariates, the presence of CAC was independently associated with FMR (OR, 1.014; 95% CI, 1.002-1.026; p = 0.019. The association was maintained even after adjusting for body mass index and waist circumference (odds ratio, 1.019; 95% confidence interval, 1.004 -1.034; P = 0.012). Conclusion: In this study, a high FMR was significantly associated with CAC. A large-scale prospective study on the association with FMR and cardiovascular diseases is necessary to confirm this relationship.


Spatial and Temporal Control of 3D Hydrogel Viscoelasticity through Phototuning.
The mechanical properties of the extracellular environment can regulate a variety of cellular functions, such as spreading, migration, proliferation, and even differentiation and phenotypic determination. Much effort has been directed at understanding the effects of the extracellular matrix (ECM) elastic modulus and, more recently, stress relaxation on cellular processes. In physiological contexts such as development, wound healing, and fibrotic disease progression, ECM mechanical properties change substantially over time or space. Dynamically tunable hydrogel platforms have been developed to spatiotemporally modulate a gel's elastic modulus. However, dynamically altering the stress relaxation rate of a hydrogel remains a challenge. Here, we present a strategy to tune hydrogel stress relaxation rates in time or space using a light-triggered tethering of poly(ethylene glycol) to alginate. We show that the stress relaxation rate can be tuned without altering the elastic modulus of the hydrogel. We found that cells are capable of sensing and responding to dynamic stress relaxation rate changes, both morphologically and through differences in proliferation rates. We also exploited the light-based technique to generate spatial patterns of stress relaxation rates in 3D hydrogels. We anticipate that user-directed control of the 3D hydrogel stress relaxation rate will be a powerful tool that enables studies that mimic dynamic ECM contexts or as a means to guide cell fate in space and time for tissue engineering applications.


Relation of T-wave alternans to mortality and nonsustained ventricular tachycardia in patients with non-ST-segment elevation acute coronary syndrome from the MERLIN-TIMI 36 trial of ranolazine versus placebo.
We explored the utility of T-wave alternans (TWA) in predicting mortality in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Maximum TWA was calculated using Modified Moving Average method from continuous electrocardiographic recordings in patients with left ventricular ejection fraction <40% and ventricular tachycardia (VT) ≥4 beats during index hospitalization or sudden cardiac death during the follow-up year and age- and sex-matched controls in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial. All patients received standard therapy for NSTEACS plus ranolazine (n = 109) or placebo (n = 101). Median follow-up was 1 year. Baseline clinical characteristics did not differ between patients with elevated TWA (≥47 μV) compared with lower levels. Patients with TWA ≥47 μV at admission had increased risk of total mortality (adjusted odds ratio [ORadj] 2.35, p = 0.04) during follow-up and VT ≥4 beats (ORadj 2.70, p = 0.01) during hospitalization with a trend toward increased cardiovascular death risk (ORadj 2.18, p = 0.07) during follow-up. In patients receiving placebo, TWA ≥47 μV on day 6 was associated with increased risk of total mortality (OR 4.12, 95% confidence interval 1.25 to 13.64, p = 0.02) and cardiovascular death (OR 4.73, p = 0.01) during follow-up. No deaths occurred among patients with TWA ≥47 μV assigned to ranolazine. In conclusion, in patients with NSTEACS and left ventricular ejection fraction <40%, TWA ≥47 μV early after admission is associated with increased risk of mortality at 1 year and with nonsustained VT during hospitalization. TWA may be useful in risk estimation in patients with NSTEACS. The possibility that TWA may serve as a therapeutic target deserves further exploration.


The Design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Trial.
Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained.


miRmapper: A Tool for Interpretation of miRNA⁻mRNA Interaction Networks.
It is estimated that 30% of all genes in the mammalian cells are regulated by microRNA (miRNAs). The most relevant miRNAs in a cellular context are not necessarily those with the greatest change in expression levels between healthy and diseased tissue. Differentially expressed (DE) miRNAs that modulate a large number of messenger RNA (mRNA) transcripts ultimately have a greater influence in determining phenotypic outcomes and are more important in a global biological context than miRNAs that modulate just a few mRNA transcripts. Here, we describe the development of a tool, "miRmapper", which identifies the most dominant miRNAs in a miRNA⁻mRNA network and recognizes similarities between miRNAs based on commonly regulated mRNAs. Using a list of miRNA⁻target gene interactions and a list of DE transcripts, miRmapper provides several outputs: (1) an adjacency matrix that is used to calculate miRNA similarity utilizing the Jaccard distance; (2) a dendrogram and (3) an identity heatmap displaying miRNA clusters based on their effect on mRNA expression; (4) a miRNA impact table and (5) a barplot that provides a visual illustration of this impact. We tested this tool using nonmetastatic and metastatic bladder cancer cell lines and demonstrated that the most relevant miRNAs in a cellular context are not necessarily those with the greatest fold change. Additionally, by exploiting the Jaccard distance, we unraveled novel cooperative interactions between miRNAs from independent families in regulating common target mRNAs; i.e., five of the top 10 miRNAs act in synergy.


Experimental gold-induced autoimmunity.
The pathogenesis of gold-induced autoimmunity and membranous glomerulopathy is not well understood. HgCl2 and D-penicillamine, other chemicals known to trigger membranous glomerulopathy in humans, induce autoimmune manifestations in Brown-Norway (BN) rats but not in Lewis (LEW) rats. These chemicals trigger T-cell clones which are specific for self class II molecules from the major histocompatibility complex and are probably responsible for the polyclonal B-cell activation observed. The aim of this work was to test the effects of aurothiopropanolsulphonate (ATPS) in BN and LEW rats. In BN rats, ATPS induced a polyclonal B-cell activation marked by lymphoproliferation, hyperimmunoglobulinaemia affecting mainly IgE, and by the production of numerous autoantibodies. A glomerulonephritis occurred, initially due to anti-glomerular basement membrane antibody deposition, and later to the formation of granular deposits, occasionally resulting in a typical membranous glomerulopathy. Self class-II-specific T-cells were found that might be responsible for the polyclonal B-cell activation. Lewis rats were free of glomerulopathy but, like BN rats, exhibited an interstitial nephritis and some degree of polyclonal B-cell activation. These findings demonstrate that, depending on the strain, ATPS triggers different B-cell clones inducing different degrees of autoimmunity.


Identification of genes related to nitrogen uptake in wine strains of Saccharomyces cerevisiae.
The yeast Saccharomyces cerevisiae is the main microorganism responsible for wine fermentation and its development influences the quality of wine. A problem affecting these types of fermentations, generating important losses in this industry, are the slow or stuck fermentations which may result from low nitrogen availability in the must. Therefore, several studies have been directed towards identifying genes involved in nitrogen metabolism using high throughput strategies which include subjecting the yeast to changes in the type or concentration of the available nitrogen source. However, this type of approach can also generate responses in the yeast that do not necessarily alter the expression of genes related to nitrogen metabolism. In this work, by using intraspecific hybridisation of wild wine yeast strains we obtained genetically and oenologically similar strains with differences in the consumption of nitrogen sources. Using the same must, the global expression patterns of these yeasts were compared by microarrays, the analysis of which identified 276 genes that varied in their expression between the strains analysed. The functional analysis of the genes with a known function indicates that some participate in nitrogen metabolism, alcoholic fermentation, ion transport and transcriptional regulation. Furthermore, differences were observed in the expression of genes which have been partially associated to nitrogen, as in the case of ZRT1 and ATO2. Interestingly, many of the genes identified have no known function or have not been previously associated to this phenotype.


Relations between health indicators and residential proximity to coal mining in West Virginia.
We used data from a survey of 16493 West Virginians merged with county-level coal production and other covariates to investigate the relations between health indicators and residential proximity to coal mining. Results of hierarchical analyses indicated that high levels of coal production were associated with worse adjusted health status and with higher rates of cardiopulmonary disease, chronic obstructive pulmonary disease, hypertension, lung disease, and kidney disease. Research is recommended to ascertain the mechanisms, magnitude, and consequences of a community coal-mining exposure effect.


Time to recovery after a hemodialysis session: impact of selected variables.
Patients maintained on hemodialysis (HD) have an impaired health-related quality of life (HRQOL). One factor that has been suggested to contribute to this impairment is the prolonged recovery time after completing a conventional HD session. The present study was designed to carefully examine the time to recovery (TTR) in patients maintained on three times/week conventional HD and evaluate the clinical and demographic features associated with the TTR. Two hundred and sixty-seven patients on conventional three times/week HD were studied during three successive HD treatments. Patients were asked how long it took them to recover from their previous session. Detailed demographic and clinical data as well as data involving the most recent HD session were reviewed. The mean ± SD age was 66.4 ± 15.7 and the mean duration of renal replacement therapy was 40.1 ± 37.6 months. The mean time to recovery was 246 ± 451 min. A multivariate regression analysis including age, gender, number of comorbidities, months on renal replacement therapy, occurrence of hypotension during dialysis, amount of ultrafiltration and duration of dialysis session revealed that none of these covariates was significantly associated with TTR from HD. The present study is important since it clarifies that the TTR after an HD session is not related to various demographic and clinical factors that one might have expected would impact on this variable.


Protective immunity against disparate tumors is mediated by a nonpolymorphic MHC class I molecule.
Current peptide-based immunotherapies for treatment of model cancers target tumor Ags bound by the classical MHC class I (class Ia) molecules. The extensive polymorphism of class Ia loci greatly limits the effectiveness of these approaches. We demonstrate in this study that the murine nonpolymorphic, nonclassical MHC class I (class Ib) molecule Q9 (Qa-2) promotes potent immune responses against multiple syngeneic tumors. We have previously shown that ectopic expression of Q9 on the surface of class Ia-negative B78H1 melanoma led to efficient CTL-mediated rejection of this tumor. In this study, we report that surface-expressed Q9 on 3LLA9F1 Lewis lung carcinoma and RMA T cell lymphoma also induces potent antitumor CTL responses. Importantly, CTL harvested from animals surviving the initial challenge with Q9-positive 3LLA9F1, RMA, or B78H1 tumors recognized and killed their cognate tumors as well as the other cancer lines. Furthermore, immunization with Q9-expressing 3LLA9F1 or RMA tumor cells established immunological memory that enhanced protection against subsequent challenge with a weakly immunogenic, Q9-bearing melanoma variant. Collectively, the generation of cross-reactive CTL capable of eliminating multiple disparate Q9-expressing tumors suggests that this nonpolymorphic MHC class I molecule serves as a restriction element for a shared tumor Ag(s) common to lung carcinoma, T cell lymphoma, and melanoma.


Intravesical Bacillus Calmette-Guerin treatment-induced sleep quality deterioration in patients with non-muscle invasive bladder cancer: functional outcome assessment based on a questionnaire survey and actigraphy.
We investigated sleep parameters and patient-reported outcomes before, during, and after induction Bacillus Calmette-Guerin therapy using questionnaires and actigraphy in patients with non-muscle invasive bladder cancer. We investigated 10 patients who received Bacillus Calmette-Guerin therapy once weekly for 8 weeks. The International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, Functional Assessment of Cancer Therapy-Bladder, and multi-item Short Form-8 tools were used to assess patient-reported outcomes. Participants completed all questionnaires before (baseline), at the 4th and 8th doses, and 1 month after the last Bacillus Calmette-Guerin dose. The MotionWatch8 was fastened to patients' waist throughout the study. Composite sleep quality was determined based on sleep duration, efficiency, and fragmentation. We observed a transient increase in frequency/nocturia subscores and the insomnia subscore. The number of patients with poor sleep quality increased from 0 (0%) at baseline to 7 (70%) at the 4th dose and to 6 (60%) patients at the 8th dose. Among 10 patients, 6 (60%) were assigned to the sleep deterioration group and 4 (40%) to the non-deterioration group. Sleep quality was restored to baseline levels in 5 of 6 patients (83%) within 1 month after the last dose in the sleep deterioration group, and the nocturia subscore of the International Prostate Symptom Score was significantly increased only in this group (P=0.03). This is the first study that confirms intravesical Bacillus Calmette-Guerin-induced sleep quality deterioration based on a questionnaire survey and actigraphy.


Protective effect of pirenoxine and U74389F on induced lipid peroxidation in mammalian lenses. An in vitro, ex vivo and in vivo study.
Oxidative stress is believed to be involved in cataract development. The protective effect of the xanthomatine derivative, pirenoxine, and the 21-aminosteroid U74389F on oxidative insult in mammalian lenses was evaluated in vitro, ex vivo and in vivo. In vitro pirenoxine and U74389F inhibited lipid peroxidation induced by iron or haemoglobin in guinea-pig homogenate lens or whole lenses. Both compounds produced the same effect when lens oxidation was induced by superoxide producing system such as xanthine/xanthine oxidase or fMLP stimulated macrophages. In all the in vitro experiments, the values of biochemical lipid peroxidation markers, such as lipid hydroperoxides or thiobarbituric reactant substances, fell to the basal values with the addition of either pirenoxine (10(-5) M) or U74389F (10(-5) M). When two drops (60 microl) of the above molecular solutions (0.005 and 0.012% in saline respectively) were instilled in rabbit eyes (every hour for 8 hours over 2 days), the extracted lenses appeared to have better defences against an in vitro iron-induced lipid peroxidation, as shown by the values of conjugated dienes and lipid soluble fluorescent substances. These values also proved to be significantly lower when the same parameters were assayed in lenses from eyes where a lipid peroxidation was induced in vivo by haemoglobin or Diquat intravitreal injection followed by instillations of pirenoxine sodium salt or U74389F solutions (2 drops of about 60 microl every hour for 8 hours over 4 days) administered topically. Polarographic and chronocoulometric measurements were also performed in order to investigate the action mechanisms of both compounds. Experimental data indicate that the pirenoxine sodium salt and U74389F may be considered effective tools for rejecting an oxidative attack on the lenses, which can finally lead to cataract formation.


Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations.
Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Fluorescence in situ hybridization on 40 cases of acute myeloid leukemia with high BCL11B mRNA expression [2.5-fold above median; 40 out of 530 cases (7.5%)] revealed 14q32 abnormalities in two additional cases. In the four BCL11B-rearranged cases the 14q32 locus was fused to different partner chromosomes. In fact, in two cases, we demonstrated that the focal 14q32 amplifications were integrated into transcriptionally active loci. The translocations involving BCL11B result in increased expression of full-length BCL11B protein. The BCL11B-rearranged acute myeloid leukemias expressed both myeloid and T-cell markers. These biphenotypic acute leukemias all carried FLT3 internal tandem duplications, a characteristic marker of acute myeloid leukemia. BCL11B mRNA expression in acute myeloid leukemia appeared to be strongly associated with expression of other T-cell-specific genes. Myeloid 32D(GCSF-R) cells ectopically expressing Bcl11b showed decreased proliferation rate and less maturation. In conclusion, by an integrated approach involving high-throughput genome-wide genotyping and gene expression profiling we identified BCL11B as a candidate oncogene in acute myeloid leukemia.