Journal articles on the topic 'Fresh and compelling evidence exception'
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1
Wang, Gang. "Design and Realization of Network Gambling Crime Investigation System." Applied Mechanics and Materials 687-691 (November 2014): 1712–15. http://dx.doi.org/10.4028/www.scientific.net/amm.687-691.1712.
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The article discusses the investigation of net gambling. In the world, according to different states have different attitude; the section concludes the illegality of net gambling. Initiation of investigation has two categories: automatic initiation and compelling initiation, we should choose the latter, but it should have exception. The specific countermeasures are collecting leads from citizens’ reports or the public security organs’ conduct. Then the public security organs should find out the truth of the case, arrest the suspects and obtain the evidence. When the investigations were concluded, the organs should remove it to procurator ate for examination, or quash the case, in accordance with the following elements: the facts, evidence and legality. At the last of the section, specific investigation countermeasures for different kinds of net gambling are discussed.
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Huang, Rong, Xiaojun Lin, Xunzhuo Xi, and Desmond Chun Yip Yuen. "The effect of earnings management on external loan price: evidence from China." International Journal of Accounting & Information Management 30, no. 2 (March 15, 2022): 277–300. http://dx.doi.org/10.1108/ijaim-11-2021-0225.
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Purpose This paper aims to explore how external creditors assess firms’ financial aggressiveness in China. Design/methodology/approach Using bank loan-specific data, the authors investigate whether firms exhibit greater costs of bank loans when they engage in earnings manipulation and whether this association changes when restrictions on lenders’ compensation are promulgated. Findings The authors find compelling evidence that bank executives charge higher premiums on firms with accrual earnings management to compensate for additional financial risk but do not charge extra loan prices for firms conducting real earnings management (REM). The authors also find that the enactment of Robust Bank Executive Compensation (REBC) enhances the vigilance of bank executives on the overall client firms’ earnings manipulation, with the exception of REM conducted by state-owned firms. Originality/value The authors extend the current literature on the cost of external loans by focusing on bank loans and the influence of REBC. This study offers implications for policymakers in China and other emerging economics to control loan default and financial risk.
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Savage, Kerry J. "Therapies for Peripheral T-Cell Lymphomas." Hematology 2011, no. 1 (December 10, 2011): 515–24. http://dx.doi.org/10.1182/asheducation-2011.1.515.
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AbstractPeripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of disorders that, for the most part, are associated with a very poor prognosis. The standard therapy for PTCLs is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or a comparable CHOP-like regimen that incorporates anthracyclines. With the exception of anaplastic lymphoma kinase–positive anaplastic large cell lymphoma (ALK+ ALCL), the cure rate for PTCLs with CHOP is low, and limited evidence suggests that anthracyclines do not improve the prognosis. However, there is no compelling evidence that any other regimen or approach is superior. It remains challenging to compare alternative therapies or treatment strategies with CHOP because the majority of data are retrospective and include diverse patient populations. Recently, prospective studies have been initiated exclusively for PTCL, and in some, select histologic subtypes are evaluated in an effort to remove heterogeneity. Encouragingly, there have been several new therapies emerging with activity in PTCLs and exciting novel combinations under consideration that will hopefully move the field forward and improve outcome in this challenging group of diseases.
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Ulviya Hajibala Azizova, Samira Arif Baghirova, Rana Rufat Rahimova, and Gulnara Sabir Dashdamirova. "Vitamin D: Structure and mechanism of action." World Journal of Biology Pharmacy and Health Sciences 9, no. 3 (March 30, 2022): 036–41. http://dx.doi.org/10.30574/wjbphs.2022.9.3.0052.
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Vitamin D has received more attention in recent years as a result of the resurgence of vitamin D deficiency and rickets as a global health issue, as well as compelling evidence in the laboratory indicating that 1,25-dihydroxy vitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin D, generates several extraskeletal biological responses such as inhibition of breast, colon, and prostate cancer cell progression; effects on the cardiovascular system; and protects against. This review covers our present knowledge of vitamin D and its bioactivation, as well as fresh findings that have altered our understanding of vitamin D activity in both classical and nonclassical target tissues. This page also assesses vitamin D's alleged involvement in extraskeletal health, provides an overview of 1,25(OH)2D3 analogs that have been created, and highlights unanswered problems.
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Silveira, RML, and B. Weiss. "Evidence for herbaceous seed dispersal by small-bodied fishes in a Pantanal seasonal wetland." Brazilian Journal of Biology 74, no. 3 (August 2014): 588–96. http://dx.doi.org/10.1590/bjb.2014.0089.
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We analysed the germination of seeds after their passage through the digestive tract of small floodplain fishes. Samples were collected in five open flooded fields of the northern Pantanal in March 2011. All fishes were sacrificed and their intestinal contents were removed. The fecal material was weighed and stored at 4°C in a GF/C filter wrapped in aluminum foil. The material was then transferred to a receptacle containing sterilised soil from the sampling area. The fecal samples were kept in a germination chamber for 68 days and then transferred to a greenhouse for another 67 days. We collected a total of 45 fish species and 1014 individuals which produced a total amount of 32g of fresh fecal mass and 11 seedlings. We were able to identify six seedlings: two Banara arguta, two Steinchisma laxa, one Hymenachne amplexicaulis and one Luziola sp.. The fish species that produced samples with seedlings were Astyanax assuncionensis, Metynnis mola, Plesiolebias glaucopterus, Acestrorhyncus pantaneiro and Anadoras wendelli. With the exception of B. arguta the remaining plant species and all fish species were not known to be associated with the seed dispersal process of these plants. We found a ratio of 0.435 seedlings.g–1 of fresh fecal material, which is 100 times higher than the amount of seedlings encountered in fresh soil mass (92,974 grams) in seed bank studies conducted in the same study area. In particular, Astyanax assuncionensis and Metynnis mola were among the most frequent and most abundant fish taxa in the area. Together with the high seed concentration in the fish fecal material, this evidence allows us to conclude that such fish species may play an important role in seed dispersal in the herbaceous plants of the Pantanal.
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King, Jaime Staples, and Benjamin W. Moulton. "Rethinking Informed Consent: The Case for Shared Medical Decision-Making." American Journal of Law & Medicine 32, no. 4 (December 2006): 429–501. http://dx.doi.org/10.1177/009885880603200401.
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In law, with rare exception such as legislative action, change is evolutionary and methodical. Unlike biomedical science where a breakthrough can quickly lead to dramatic changes in medical practice, legal precedent is more adherent and must evolve either through the legislative process or on a court by court basis in case law. Nevertheless, compelling evidence will pave the road to change within the law. Health care research conducted over the last three decades has produced a body of empirical evidence that suggests an overhaul of our current legal standards of informed consent is overdue.This article uses health services research to examine the fundamental assumptions of our current informed consent laws and propose legal reform. Much has been written on how to bring the law to bear on medical practice in order to improve patient rights and protect physicians, but far less has been done to bring the practice of medicine to inform our legal standards. Prior legal scholarship on informed consent has made arguments regarding reform from both ethical and legal perspectives; however, only a small few have incorporated clinical and health services research as well as ethical and legal principles to analyze informed consent.
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Mainville, Denise Y., Thomas Reardon, and Elizabeth M. M. Q. Farina. "Scale, scope, and specialization effects on retailers’ procurement strategies: evidence from the fresh produce markets of São Paulo." Revista de Economia e Sociologia Rural 46, no. 1 (March 2008): 207–27. http://dx.doi.org/10.1590/s0103-20032008000100009.
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Worldwide, the emergence of large supermarket chains in food retail markets is often associated with the marginalization of smaller retailers. A notable exception exists in Brazil, however, where small retailers have held their place in the market and recently even gained ground. The literature investigating how retail concentration has affected agrifood chains has focused activities of the largest retail chains, implicitly holding the scale, scope and specialization of retailers’ input needs constant, and overlooking the influence of these factors on retailers’ procurement strategies. This paper tests hypotheses regarding these variables’ effects on retailers’ fresh produce procurement strategies. Data is drawn from a survey of retailers in metropolitan São Paulo. The research results provide insight into factors underlying retailers’ procurement strategy choices and tradeoffs among options. The results support the fundamental hypothesis of the paper that research on the competitive strategies of smaller retailers in a context of market domination by large retailers should not focus exclusively on the degree to which the smaller retailers imitate the larger retailers rather it should account for the possibility that the underlying characteristics of the retailers may make diverse competitive strategies appropriate.
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Lippke, Richard L. "Modifying Double Jeopardy." New Criminal Law Review 15, no. 4 (2012): 511–41. http://dx.doi.org/10.1525/nclr.2012.15.4.511.
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The question addressed concerns the defensibility of that part of the Constitutional ban on double jeopardy which forbids the state from retrying criminal defendants for the same crimes of which they have earlier been acquitted. A procedure for permitting the retrial of such defendants is developed and defended. This procedure would allow acquittals to be quashed if state officials can convince a court that they have fresh, reliable, and compelling evidence of a person's guilt. The stock arguments in favor of a ban on double jeopardy are considered in light of this proposal and shown to be unpersuasive. A variety of other arguments against the proposal are likewise shown to be unconvincing. Particular attention is paid to the concern that the procedure might produce convictions of innocent people. This possibility is shown to be remote and thus not a reasonable ground for refusing to attempt to correct substantively mistaken acquittals.
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Panagariya, Arvind. "A Re-examination of the Infant Industry Argument for Protection." Margin: The Journal of Applied Economic Research 5, no. 1 (February 2011): 7–30. http://dx.doi.org/10.1177/097380101000500102.
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Though a logically tight case for infant industry protection has never been made, proprotection authors have claimed its truth since at least its statement by Alexander Hamilton in 1791. In the 1970s and the 1980s, the argument had receded into the background following its influential critiques by trade economists James Meade, Harry Johnson and Robert Baldwin. But globalisation critics have recently revived it giving it new guises. This requires a fresh response from pro-free trade economists so that the fog is removed yet again and clear thinking restored. Accordingly, in this paper, I revisit the argument and its logical flaws. I demonstrate that the new packaging provided by proprotection authors cannot hide the fundamental logical flaws in the argument. Nor is there compelling evidence of successful infant industry promotion once the costs and benefits are both taken into account instead of just the benefits. The argument is often pegged on externalities. But once the precise source of the externality is pinned down, protection as an instrument to correct it turns out to be ineffective.
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Morlock, Glenn P., Frances C. Tyrrell, Dorothy Baynham, Vincent E. Escuyer, Nicole Green, Youngmi Kim, Patricia A. Longley-Olson, et al. "Using Reduced Inoculum Densities of Mycobacterium tuberculosis in MGIT Pyrazinamide Susceptibility Testing to Prevent False-Resistant Results and Improve Accuracy: A Multicenter Evaluation." Tuberculosis Research and Treatment 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/3748163.
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The primary platform used for pyrazinamide (PZA) susceptibility testing of Mycobacterium tuberculosis is the MGIT culture system (Becton Dickinson). Since false-resistant results have been associated with the use of this system, we conducted a multicenter evaluation to determine the effect of using a reduced cell density inoculum on the rate of false resistance. Two reduced inoculum densities were compared with that prescribed by the manufacturer (designated as “BD” method). The reduced inoculum methods (designated as “A” and “C”) were identical to the manufacturer’s protocol in all aspects with the exception of the cell density of the inoculum. Twenty genetically and phenotypically characterized M. tuberculosis isolates were tested in duplicate by ten independent laboratories using the three inoculum methods. False-resistant results declined from 21.1% using the standard “BD” method to 5.7% using the intermediate (“A”) inoculum and further declined to 2.8% using the most dilute (“C”) inoculum method. The percentages of the resistant results that were false-resistant declined from 55.2% for the “BD” test to 28.8% and 16.0% for the “A” and “C” tests, respectively. These results represent compelling evidence that the occurrence of false-resistant MGIT PZA susceptibility test results can be mitigated through the use of reduced inoculum densities.
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Njoku, Kelechi, Caroline J. J. Sutton, Anthony D. Whetton, and Emma J. Crosbie. "Metabolomic Biomarkers for Detection, Prognosis and Identifying Recurrence in Endometrial Cancer." Metabolites 10, no. 8 (July 31, 2020): 314. http://dx.doi.org/10.3390/metabo10080314.
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Metabolic reprogramming is increasingly recognised as one of the defining hallmarks of tumorigenesis. There is compelling evidence to suggest that endometrial cancer develops and progresses in the context of profound metabolic dysfunction. Whilst the incidence of endometrial cancer continues to rise in parallel with the global epidemic of obesity, there are, as yet, no validated biomarkers that can aid risk prediction, early detection, prognostic evaluation or surveillance. Advances in high-throughput technologies have, in recent times, shown promise for biomarker discovery based on genomic, transcriptomic, proteomic and metabolomic platforms. Metabolomics, the large-scale study of metabolites, deals with the downstream products of the other omics technologies and thus best reflects the human phenotype. This review aims to provide a summary and critical synthesis of the existing literature with the ultimate goal of identifying the most promising metabolite biomarkers that can augment current endometrial cancer diagnostic, prognostic and recurrence surveillance strategies. Identified metabolites and their biochemical pathways are discussed in the context of what we know about endometrial carcinogenesis and their potential clinical utility is evaluated. Finally, we underscore the challenges inherent in metabolomic biomarker discovery and validation and provide fresh perspectives and directions for future endometrial cancer biomarker research.
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King, Christopher R., Joanna Abraham, Thomas G. Kannampallil, Bradley A. Fritz, Arbi Ben Abdallah, Yixin Chen, Bernadette Henrichs, et al. "Protocol for the Effectiveness of an Anesthesiology Control Tower System in Improving Perioperative Quality Metrics and Clinical Outcomes: the TECTONICS randomized, pragmatic trial." F1000Research 8 (November 29, 2019): 2032. http://dx.doi.org/10.12688/f1000research.21016.1.
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Introduction: Perioperative morbidity is a public health priority, and surgical volume is increasing rapidly. With advances in technology, there is an opportunity to research the utility of a telemedicine-based control center for anesthesia clinicians that assess risk, diagnoses negative patient trajectories, and implements evidence-based practices. Objectives: The primary objective of this trial is to determine whether an anesthesiology control tower (ACT) prevents clinically relevant adverse postoperative outcomes including 30-day mortality, delirium, respiratory failure, and acute kidney injury. Secondary objectives are to determine whether the ACT improves perioperative quality of care metrics including management of temperature, mean arterial pressure, mean airway pressure with mechanical ventilation, blood glucose, anesthetic concentration, antibiotic redosing, and efficient fresh gas flow. Methods and analysis: We are conducting a single center, randomized, controlled, phase 3 pragmatic clinical trial. A total of 58 operating rooms are randomized daily to receive support from the ACT or not. All adults (eighteen years and older) undergoing surgical procedures in these operating rooms are included and followed until 30 days after their surgery. Clinicians in operating rooms randomized to ACT support receive decision support from clinicians in the ACT. In operating rooms randomized to no intervention, the current standard of anesthesia care is delivered. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 99% confidence intervals; p-values <0.005 will be reported as providing compelling evidence, and p-values between 0.05 and 0.005 will be reported as providing suggestive evidence. Registration: TECTONICS is registered on ClinicalTrials.gov, NCT03923699; registered on 23 April 2019.
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Katz, Laura A. "Recent events dominate interdomain lateral gene transfers between prokaryotes and eukaryotes and, with the exception of endosymbiotic gene transfers, few ancient transfer events persist." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1678 (September 26, 2015): 20140324. http://dx.doi.org/10.1098/rstb.2014.0324.
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While there is compelling evidence for the impact of endosymbiotic gene transfer (EGT; transfer from either mitochondrion or chloroplast to the nucleus) on genome evolution in eukaryotes, the role of interdomain transfer from bacteria and/or archaea (i.e. prokaryotes) is less clear. Lateral gene transfers (LGTs) have been argued to be potential sources of phylogenetic information, particularly for reconstructing deep nodes that are difficult to recover with traditional phylogenetic methods. We sought to identify interdomain LGTs by using a phylogenomic pipeline that generated 13 465 single gene trees and included up to 487 eukaryotes, 303 bacteria and 118 archaea. Our goals include searching for LGTs that unite major eukaryotic clades, and describing the relative contributions of LGT and EGT across the eukaryotic tree of life. Given the difficulties in interpreting single gene trees that aim to capture the approximately 1.8 billion years of eukaryotic evolution, we focus on presence–absence data to identify interdomain transfer events. Specifically, we identify 1138 genes found only in prokaryotes and representatives of three or fewer major clades of eukaryotes (e.g. Amoebozoa, Archaeplastida, Excavata, Opisthokonta, SAR and orphan lineages). The majority of these genes have phylogenetic patterns that are consistent with recent interdomain LGTs and, with the notable exception of EGTs involving photosynthetic eukaryotes, we detect few ancient interdomain LGTs. These analyses suggest that LGTs have probably occurred throughout the history of eukaryotes, but that ancient events are not maintained unless they are associated with endosymbiotic gene transfer among photosynthetic lineages.
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Timoshenko, Konstantin. "RUSSIAN PUBLIC SECTOR REFORM: THE IMPACT ON UNIVERSITY ACCOUNTING." Journal of Business Economics and Management 9, no. 2 (June 30, 2008): 133–44. http://dx.doi.org/10.3846/1611-1699.2008.9.133-144.
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The last few decades have witnessed substantial efforts to reinvent the state worldwide. The Russian state is no exception to this global trend. At the outset of a new millennium, the need for renewal of the post‐Soviet model of the state has been acknowledged, and an up‐to‐date reform package has been promoted by the central government. This has encompassed the reconstruction of public sector accounting. Given the paucity of consistent research efforts on the topic, this article seeks to describe and analyze, and by so doing, contribute to knowledge about Russian public sector accounting in times of change. To tackle the general purpose, two levels are incorporated in this study to link reform initiatives for the government as a whole with those endeavours to implement them in one state‐sponsored university of Russian tertiary education. The major questions to be addressed are of whether, why, and how changes at the central government level have penetrated down to the university and extended to its accounting system. The evidence gathered in this paper reveals that a new Russian public sector ideology has markedly been affected by overseas developments in the shape of large international organizations. However, no compelling evidence has been documented in this research as unveiling that changes at the macro‐level have penetrated down to the university to any significant extent. This study concludes that launching a new version of accounting by the Russian state can be regarded as more of a symbol of legitimacy for the university rather than of an actual financial management tool.
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Steinnes, Eiliv, and Andrew J. Friedland. "Metal contamination of natural surface soils from long-range atmospheric transport: Existing and missing knowledge." Environmental Reviews 14, no. 3 (September 1, 2006): 169–86. http://dx.doi.org/10.1139/a06-002.
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This review focuses on the long-range atmospheric transport of metals to organic-rich surface soils (mostly 50–90% organic matter) in the temperate, coniferous, and boreal zones of North America and Europe. From various air-pollution related measurements (air, precipitation, moss, peat cores) Pb and Zn are known to be transported long distances in the air in large amounts. Arsenic, Cd, Hg, Sb, and Se are also typical representatives of long-range transported air masses, and there is evidence that Ag, Bi, In, Mo, Tl, and W belong to this group of elements. Through the use of “environmental archives” such as ice and peat cores it has become evident that long-range transport of pollutants and associated contamination of natural surfaces is not just a recent phenomenon. There is compelling evidence for widespread enrichment of surface soil horizons in Pb from long-range transport, and many studies support enrichment of Zn. Mercury is also generally elevated by anthropogenic emissions over natural levels in organic-rich surface soils, whereas results for Cd are less conclusive. There is evidence that As, Se, Ag, Mo, In, Sb, W, Tl, and Bi all are subject to some enrichment in organic-rich surface soils from long-range atmospheric transport, but studies are still few for most of these elements. With the exception of Pb, little is known about residence times of the elements in the organic-rich surface horizon, and more research is needed on this topic. Further studies are desirable on the temporal and spatial trends in supply of the above elements, which are poorly known in large parts of the northern temperate zone.Key words: natural soils, metals, long-range atmospheric transport, organic matter, lead, zinc, cadmium, mercury.
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Prentice, A. "Diet, nutrition and the prevention of osteoporosis." Public Health Nutrition 7, no. 1a (February 2004): 227–43. http://dx.doi.org/10.1079/phn2003590.
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AbstractObjective:To review the evidence on diet and nutrition relating to osteoporosis and provide recommendations for preventing osteoporosis, in particular, osteopototic fracture.Approach:Firstly, to review the definition, diagnosis and epidemiology of osteoporosis, to discuss the difficulties in using bone mineral density to define osteoporosis risk in a world-wide context and to propose that fragility fracture should be considered as the disease endpoint. Secondly, to provide an overview of the scientific data, the strengths and weaknesses of the evidence and the conceptual difficulties in interpreting studies linking diet, nutrition and osteoporosis. The following were considered: calcium, vitamin D, phosphorus, magnesium, protein and fluorine. Other potential dietary influences on bone health were also discussed, including vitamins, trace elements, electrolytes, acid–base balance, phyto-oestrogens, vegetarianism and lactose intolerance.Conclusions:There is insufficient knowledge linking bone mineral status, growth rates or bone turnover in children and adolescents to long-term benefits in old age for these indices to be used as markers of osteoporotic disease risk. For adults, the evidence of a link between intakes of any dietary component and fracture risk is not sufficiently secure to make firm recommendations, with the exception of calcium and vitamin D. For other aspects of the diet, accumulating evidence suggests that current healthy-eating advice to decrease sodium intake, to increase potassium intake, and to consume more fresh fruits and vegetables is unlikely to be detrimental to bone health and may be beneficial.
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Millar, Helen, and Mohammed T. Abou-Saleh. "Multimorbidity in Mentally Ill People: The Need for a Person-centered Integrated Approach." International Journal of Person Centered Medicine 5, no. 1 (June 25, 2015): 28–33. http://dx.doi.org/10.5750/ijpcm.v5i1.507.
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The need for person-centered integrated care is particularly compelling for people who experience multimorbidity. The concept of multimorbidity has attracted increasing interest in the past decade with the recognition of multiple burdens of disease and their escalating costs for the individual and the community. It is evident in clinical practice that multimorbidity has become the norm rather than the exception, occurring in an increasingly younger population particularly in areas of socioeconomic deprivation and in low income countries. It is now well established that the mentally ill have a markedly reduced life expectancy due to predominantly cardiovascular and metabolic diseases. The combination of a chronic medical condition and a mental health problem presents specific complex challenges for the single disease model of care which continues to prevail as the current delivery system in which health care professionals are trained and operate. The growing evidence and experience for adopting an integrated collaborative person-centered approach demonstrates the need for a more effective model of care which is individualised, and focused on patient engagement to prevent disease and manage multiple conditions systematically. Given the limited resources in our current health care systems, this approach requires innovation and redesign of the system to provide comprehensive person-centered care encompassing early detection, co-ordinated multidisciplinary working across specialities as well as between primary and secondary care with easy access to basic healthy lifestyle care programs.
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Howard, A. D. P., A. P. Whitworth, M. J. Griffin, K. A. Marsh, and M. W. L. Smith. "A PPMAP analysis of the filamentary structures in Ophiuchus L1688 and L1689." Monthly Notices of the Royal Astronomical Society 504, no. 4 (April 30, 2021): 6157–78. http://dx.doi.org/10.1093/mnras/stab1166.
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ABSTRACT We use the Point Process MAPping (PPMAP) algorithm to reanalyse the Herschel and SCUBA-2 observations of the L1688 and L1689 subregions of the Ophiuchus molecular cloud. PPMAP delivers maps with high resolution (here 14 arcsec, corresponding to ${\sim}0.01\, {\rm pc}$ at ${\sim}140\, {\rm pc}$), by using the observations at their native resolutions. PPMAP also delivers more accurate dust optical depths, by distinguishing dust of different types and at different temperatures. The filaments and pre-stellar cores almost all lie in regions with $N_{\rm H_2}\gtrsim 7\times 10^{21}\, {\rm cm}^{-2}$ (corresponding to AV ≳ 7). The dust temperature, T, tends to be correlated with the dust opacity index, β, with low T and low β concentrated in the interiors of filaments. The one exception to this tendency is a section of filament in L1688 that falls – in projection – between the two B stars: S1 and HD147889; here T and β are relatively high, and there is compelling evidence that feedback from these two stars has heated and compressed the filament. Filament fwhms are typically in the range $0.10$ to $0.15\, {\rm pc}$. Most filaments have line-densities in the range $25$ to $65\, {\rm M_{\odot }\, pc^{-1}}$. If their only support is thermal gas pressure, and the gas is at the canonical temperature of $10\, {\rm K}$, the filaments are highly supercritical. However, there is some evidence from ammonia observations that the gas is significantly warmer than this, and we cannot rule out the possibility of additional support from turbulence and/or magnetic fields. On the basis of their spatial distribution, we argue that most of the starless cores are likely to disperse (rather than evolving to become pre-stellar).
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Kirov, Sylvia M., Lisa A. O’Donovan, and Kevin Sanderson. "Functional Characterization of Type IV Pili Expressed on Diarrhea-Associated Isolates of Aeromonasspecies." Infection and Immunity 67, no. 10 (October 1, 1999): 5447–54. http://dx.doi.org/10.1128/iai.67.10.5447-5454.1999.
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ABSTRACT Our past work has shown that long, flexible type IV pili (single or in bundles) are the predominant pili expressed on fecal isolates of diarrhea-associated species of Aeromonas (Aeromonas veronii biovar sobria and A. caviae). They represent a family of type IV pili which we have designated Bfp (for bundle-forming pili). Reports from Japan suggest that Bfp are intestinal colonization factors. This study presents compelling evidence to support this conclusion. Aeromonas bacteria and/or Bfp purified from a strain of A. veronii biovar sobria were shown to adhere to epithelial and intestinal cell lines, freshly isolated human enterocytes, and fresh and fixed human and rabbit intestinal tissues, as determined by light and electron microscopy and immunohistochemical detection. Removal of Bfp by mechanical means decreased adhesion to cell lines by up to 80%. Purified Bfp blocked adhesion of the test strain to intestinal cells in a dose-dependent manner. Adhesion was also blocked by the Fab fraction of anti-Bfp immunoglobulin G. Moreover, ultrastructural studies (ruthenium red staining and transmission and scanning electron microscopy) demonstrated for the first time that Aeromonasadhesion to human enterocytes is pilus mediated and suggested that Bfp may also promote colonization by forming bacterium-to-bacterium linkages. Bfp-positive isolates examined for type IV pilus-mediated twitching motility in agar and slide culture assays developed forPseudomonas aeruginosa did not, however, exhibit this function.
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Bull, Caroline, Damien Belobrajdic, Sara Hamzelou, Darren Jones, Wayne Leifert, Rocío Ponce-Reyes, Netsanet Shiferaw Terefe, Gemma Williams, and Michelle Colgrave. "How Healthy Are Non-Traditional Dietary Proteins? The Effect of Diverse Protein Foods on Biomarkers of Human Health." Foods 11, no. 4 (February 11, 2022): 528. http://dx.doi.org/10.3390/foods11040528.
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Future food security for healthy populations requires the development of safe, sustainably-produced protein foods to complement traditional dietary protein sources. To meet this need, a broad range of non-traditional protein foods are under active investigation. The aim of this review was to evaluate their potential effects on human health and to identify knowledge gaps, potential risks, and research opportunities. Non-traditional protein sources included are algae, cereals/grains, fresh fruit and vegetables, insects, mycoprotein, nuts, oil seeds, and legumes. Human, animal, and in vitro data suggest that non-traditional protein foods have compelling beneficial effects on human health, complementing traditional proteins (meat/poultry, soy, eggs, dairy). Improvements in cardiovascular health, lipid metabolism, muscle synthesis, and glycaemic control were the most frequently reported improvements in health-related endpoints. The mechanisms of benefit may arise from their diverse range of minerals, macro- and micronutrients, dietary fibre, and bioactive factors. Many were also reported to have anti-inflammatory, antihypertensive, and antioxidant activity. Across all protein sources examined, there is a strong need for quality human data from randomized controlled intervention studies. Opportunity lies in further understanding the potential effects of non-traditional proteins on the gut microbiome, immunity, inflammatory conditions, DNA damage, cognition, and cellular ageing. Safety, sustainability, and evidence-based health research will be vital to the development of high-quality complementary protein foods that enhance human health at all life stages.
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Langlands, Rebecca. "Latin Literature." Greece and Rome 60, no. 2 (September 16, 2013): 320–25. http://dx.doi.org/10.1017/s0017383513000132.
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Among this latest batch of books to review are a number whose endeavour, very much to my own taste, is intellectual and cultural history through the study of Latin literature. Cream of the crop is Craig Williams’ study of Roman friendship. Admirers of Williams’ excellent Roman Homosexuality, recently reissued in second edition, will recognize the approach; this is a theoretically informed and meticulously argued work of cultural history that also shows fine appreciation of philological, linguistic, and literary issues. In Chapter 1 (Men and Women), Williams has a simple and compelling point to make: basing their idealization of friendship on our male-authored ancient literary texts (Cicero's De amicitia, Seneca's Letters), the great thinkers of Western civilization have asserted that ideal friendship is a man's game, and even that women are by and large incapable of real friendship, at the very least being excluded from the most interesting parts of friendship's history. As Williams shows, the epigraphic evidence tells a different story; here we can gain a new appreciation of friendships between women, and indeed between men and women. In its divergence from the well-trodden literary tradition, the epigraphic material opens up new ways of understanding the ancient world, but it can also be used to bring a fresh perspective to familiar literary texts, especially when one is as open-minded and attentive to linguistic nuance as Williams. Chapter 2 explores some of the key conceptual issues and themes related to the (vexed) distinction between amor and amicitia, and then in Chapter 3 Williams turns to the close reading of particular Latin texts, bringing his new interpretative framework to Catullus, Horace, Virgil, and Propertius, Petronius’ Satyricon, and the letters of Cicero and of Fronto. The fourth and final chapter, ‘Friendship and the Grave’, turns again to the epigraphic evidence, and funerary inscriptions in particular, where friends are shown to play an important role in the commemoration of the dead, usually associated in the Western tradition with close family. Williams’ work showcases Classics as a vitally and productively interdisciplinary academic subject, where significant new readings can be achieved with the right methodologies and approach. He has some big claims to make about Roman society, of which ancient historians will certainly want to take note, but his fresh analysis of familiar literary texts is also highly illuminating and the book has many smaller-scale insights to offer as well.
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NISHIOKA, KENJI. "Scots and Galwegians in the ‘peoples address’ of Scottish Royal Charters." Scottish Historical Review 87, no. 2 (October 2008): 206–32. http://dx.doi.org/10.3366/e0036924108000139.
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The ‘peoples address’ (otherwise referred to as the ‘racial address’ or the ‘nation address’) was an occasional feature of royal charters until the 1170s. The components vary, with English, French and Scots appearing frequently, Galwegians less so, and Welsh very rarely. The combination of peoples found in a charter has been explained in terms of the places mentioned in the document. This remains an important consideration in the reign of David I, although hitherto it has not accounted for all the evidence. In this article a fresh examination is made of the way different combinations of peoples appear in charter-addresses. It is argued that, with the exception of a few instances, mainly where the formula has been copied from an earlier charter relating to the same transaction, a pattern of development can be discerned: (i) in David I's reign Scots are included not only if the charter relates to Scotland north of the Forth, but also if the charter was produced in the area north of the Lammermuirs; (ii) in the reign of Mael Coluim IV Scots became a general feature of the ‘peoples address’; and (iii) from 1161/2 Galwegians also become a general feature. The article concludes with some reflections on what this suggests about an emerging unification of the kingdom.
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Wendland, Jürgen. "Lager Yeast Comes of Age." Eukaryotic Cell 13, no. 10 (August 1, 2014): 1256–65. http://dx.doi.org/10.1128/ec.00134-14.
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ABSTRACTAlcoholic fermentations have accompanied human civilizations throughout our history. Lager yeasts have a several-century-long tradition of providing fresh beer with clean taste. The yeast strains used for lager beer fermentation have long been recognized as hybrids between twoSaccharomycesspecies. We summarize the initial findings on this hybrid nature, the genomics/transcriptomics of lager yeasts, and established targets of strain improvements. Next-generation sequencing has provided fast access to yeast genomes. Its use in population genomics has uncovered many more hybridization events withinSaccharomycesspecies, so that lager yeast hybrids are no longer the exception from the rule. These findings have led us to propose network evolution withinSaccharomycesspecies. This “web of life” recognizes the ability of closely related species to exchange DNA and thus drain from a combined gene pool rather than be limited to a gene pool restricted by speciation. Within the domesticated lager yeasts, two groups, the Saaz and Frohberg groups, can be distinguished based on fermentation characteristics. Recent evidence suggests that these groups share an evolutionary history. We thus propose to refer to the Saaz group asSaccharomyces carlsbergensisand to the Frohberg group asSaccharomyces pastorianusbased on their distinct genomes. New insight into the hybrid nature of lager yeast will provide novel directions for future strain improvement.
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Moore, Christopher S., Matthew J. Ruocchio, and April M. H. Blakeslee. "Distribution and population structure in the naked goby Gobiosoma bosc (Perciformes: Gobiidae) along a salinity gradient in two western Atlantic estuaries." PeerJ 6 (August 7, 2018): e5380. http://dx.doi.org/10.7717/peerj.5380.
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Many species of fish produce larvae that undergo a prolonged dispersal phase. However, evidence from a number of recent studies on demersal fishes suggests that the dispersal of propagules may not be strongly correlated with gene flow. Instead, other factors like larval behavior and the availability of preferred settlement habitat may be more important to maintaining population structure. We used an ecologically important benthic fish species, Gobiosoma bosc (naked goby), to investigate local and regional scale population structure and gene flow along a salinity gradient (∼3 ppt to ∼18 ppt) in two North Carolina estuaries. G. bosc is an abundant and geographically widespread species that requires complex but patchy microhabitat (e.g. oyster reefs, rubble, woody debris) for reproduction and refuge. We sequenced 155 fish from 10 sites, using a common barcoding gene (COI). We also included recent sequence data from GenBank to determine how North Carolina populations fit into the larger biogeographic understanding of this species. In North Carolina, we found a significant amount of gene flow within and between estuaries. Our analysis also showed high predicted genetic diversity based upon a large number of rare haplotypes found within many of our sampled populations. Moreover, we detected a number of new haplotypes in North Carolina that had not yet been observed in prior work. Sampling along a salinity gradient did not reveal any significant positive or negative correlations between salinity and genetic diversity, nor the proportion of singleton haplotypes, with the exception of a positive correlation between salinity standard deviation and genetic diversity. We also found evidence that an introduced European population of naked gobies may have originated from an Atlantic source population. Altogether, this system offers a compelling way to evaluate whether factors other than dispersal per se mediate recruitment in an estuarine-dependent species of fish with a larval dispersal phase. It also demonstrates the importance of exploring both smaller and larger scale population structure in marine organisms to better understand local and regional patterns of population connectivity and gene flow.
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Protheroe, R. J. "The Status of Ultra-High-Energy Gamma-Ray Observations." International Astronomical Union Colloquium 142 (1994): 883–88. http://dx.doi.org/10.1017/s0252921100078258.
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AbstractIn 1983 Samorski and Stamm found evidence of ultra-high-energy (UHE) gamma-ray emission from Cygnus X-3 in archival data from the Kiel air shower array. The emission appeared to be emitted only at one phase in the binary orbit. The Kiel array was sensitive to air showers generated by particles with energies above 3 × 1015 eV. Their discovery led to searches in archival data from other arrays for evidence of UHE emission from Cygnus X-3 and other potential sources in the Galaxy, and to the construction of new air shower arrays dedicated to UHE astronomy.In the mid 1980s many groups around the world claimed detections of Cygnus X-3, Hercules X-1, Vela X-1, and other objects. Cygnus X-3 is strongly variable at all wavelengths, and so it would be surprising if this variability did not extend to UHE gamma-rays also. This indeed appeared to be the case, and in the mid to late 1980s the UHE gamma-ray output showed a steady decline apart from transient UHE emission following giant radio flares. With the exception of possible detections above 1017 eV by the Fly’s Eye and Akeno Array, I am unaware of any statistically compelling claimed detections of this source reported over the past 4 years. The new arrays—CASA-MIA and SPASE—have not detected any of the claimed sources, and it seems likely that at least some of these early claims may have been premature. However, although none of the observations taken alone was of extremely high statistical significance, the observations of Cygnus X-3 by different groups showed a consistency which I feel cannot be ascribed to chance alone. The observations of Cygnus X-3 and the Crab Nebula/Pulsar are reviewed with particular reference to the results published during the last 5 years.Subject headings: gamma rays: observations — pulsars: individual (Crab Nebula) — stars: individual (Cygnus X-3)
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Battar, Saraswathy. "A Peacock That Does Not Show Its Feathers Is Not Much Different From a Turkey: On Being a Physician Executive for 25 Years." Innovation in Aging 4, Supplement_1 (December 1, 2020): 38–39. http://dx.doi.org/10.1093/geroni/igaa057.125.
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Abstract Compelling common threads in the fabric of being an academic and clinical geriatrician, VA health care executive and physician champion for VIONE – a national medication deprescribing project that was launched at 59 VA programs across the nation will be presented in a thought provoking, objective, evidence based and legacy oriented format. Highlights include a)success factors b)networking c) effective presentations d) lessons learned e)implementing elements of High Performance Delivery Model (HPDM), f)transforming ideas into actions that help rise and shine g) creating a legacy h)survey readiness h) keeping the main thing the main thing i) understanding others and helping others understand you. Making significant contributions in career is important. How the work is captured, projected, made visible as a viable, actionable solution to a critical and significant mission critical problem, strategic engagement with stakeholders, implementation with measurable outcomes, passionate engagement while being an affirmative, non-controversial leader who is eager, willing, available, capable and knowledgeable etc., are some of the other non-negotiable aspects of getting work recognized. Experiences shared include creating VIONE – a medication deprescribing project that won VA USH Shark Tank competition as a Gold Status Fellow with outcomes such as over 95,000 veterans impacted, over 194,000 non-essential medications deprescribed with accomplished cost savings of over 9.6 million US dollars in 4 years. This profound journey taught me the importance of effectively displaying worthy work with global relevance with dignity, credibility, pride, persuasion, leadership, efficiency, teamwork, art of persuasion, ponder, recharge, rejuvenate and start fresh – time and again.
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Carafano, James Jay. "William III and the Negative Voice." Albion 19, no. 4 (1987): 509–25. http://dx.doi.org/10.2307/4049472.
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A fresh interpretation of King William III's employment of the royal veto provides new insights into the political and constitutional issues of his reign. The veto, or the crown's negative voice as it was called by contemporaries, is a particularly fruitful subject for study in charting the course of politics in seventeenth century England. The employment of the veto offers an accurate barometer for measuring political and constitutional change. It addresses the key issue of sovereignty—who makes law? King or Parliament? It is surprising, therefore, that historians have neglected to examine the implications of William's employment of the veto. As a result, their conclusions about the veto are not supported by a full analysis of the available evidence. What they have overlooked is that a close examination of the bills the king rejected, and of contemporary views of the royal prerogative, demonstrates that underneath the turmoil of Williamite politics lay a stable foundation built on the settlement achieved at the Revolution of 1688/9.During his brief rule William III rejected a significant number of bills. Between 1692 and 1696 he vetoed five public bills: the Judges, Royal Mines, Triennial, Place, and MP Qualifications Bills. Previous Tudor and Stuart monarchs, with the exception of Queen Elizabeth I, only infrequently invoked the crown's right to refuse legislation. Queen Anne, who followed William to the throne, vetoed only one bill. She was the last monarch to employ this prerogative, although it remains theoretically a legitimate royal power.
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Huang, Tingting, Alexander Ploner, Ellen T. Chang, Qing Liu, Yonglin Cai, Zhe Zhang, Guomin Chen, et al. "Dietary patterns and risk of nasopharyngeal carcinoma: a population-based case-control study in southern China." American Journal of Clinical Nutrition 114, no. 2 (May 8, 2021): 462–71. http://dx.doi.org/10.1093/ajcn/nqab114.
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ABSTRACT Background Dietary factors, such as consumption of preserved foods, fresh vegetables, and fruits, have been linked to the risk of nasopharyngeal carcinoma (NPC). However, little is known about associations between dietary patterns and the risk of NPC in NPC-endemic areas. Objectives We aimed to evaluate whether dietary patterns are associated with NPC risk. Methods We studied 2554 newly diagnosed NPC patients aged 20–74 y living in 3 endemic regions of southern China, and 2648 population-based controls frequency-matched to case patients by age, sex, and region, between 2010 and 2014. Dietary components were derived from food frequency data in adulthood and adolescence using principal component analysis. Four dietary components were identified and highly similar in adulthood and adolescence. We used multivariable unconditional logistic regression to calculate ORs with 95% CIs for the association between dietary patterns and NPC risk. Results Compared with the lowest quartile, individuals in the highest quartile of the “plant-based factor” in adulthood had a 52% (OR: 0.48; 95% CI: 0.38, 0.59) decreased risk of NPC, and those in the highest quartile of the “animal-based factor” had a >2-fold (OR: 2.26; 95% CI: 1.85, 2.77) increased risk, with a monotonic dose-response trend (P-trend < 0.0001). Similar but weaker associations were found in adolescence. High intakes of the “preserved-food factor” were associated with increased NPC risk in both periods, although stronger associations were found in adolescence. Results from joint analysis and sensitivity analyses indicated that dietary factors in adulthood might be more stable and robust predictors of NPC risk than those in adolescence. Conclusions Our results deliver compelling evidence that plant- and animal-based dietary factors are associated with NPC risk, and provide more insights on the associations of diets and cancer risk that may assist healthy diet recommendations.
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Wang, Wang, Ming Yan, Ghazal Aarabi, Ulrike Peters, Marcus Freytag, Martin Gosau, Ralf Smeets, and Thomas Beikler. "Cultivation of Cryopreserved Human Dental Pulp Stem Cells—A New Approach to Maintaining Dental Pulp Tissue." International Journal of Molecular Sciences 23, no. 19 (September 29, 2022): 11485. http://dx.doi.org/10.3390/ijms231911485.
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Human dental pulp stem cells (hDPSCs) are multipotent mesenchymal stem cells (MSCs) that are capable of self-renewal with multilineage differentiation potential. After being cryopreserved, hDPSCs were reported to maintain a high level of proliferation and multi-differentiation abilities. In order to optimize cryopreservation techniques, decrease storage requirements and lower contamination risks, the feasibility of new whole-tooth cryopreservation and its effects on hDPSCs were tested. The survival rates, morphology, proliferation rates, cell activity, surface antigens and differentiation abilities of hDPSCs isolated from fresh teeth were compared with those of one-month cryopreserved teeth in 5% and 10% DMSO. The data of the present study indicated that the new cryopreservation approach did not reduce the capabilities or stemness of hDPSCs, with the exception that it extended the first appearance time of hDPSCs in the teeth that were cryopreserved in 10% DMSO, and reduced their recovery rate. With the novel strategy of freezing, the hDPSCs still expressed the typical surface markers of MSCs and maintained excellent proliferation capacity. Three consecutive weeks of osteogenic and adipogenic induction also showed that the expression of the key genes in hDPSCs, including lipoprotein lipase (LPL), peroxisome proliferator-activated receptor-γ (PPAR-γ), alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), type I collagen (COL I) and osteocalcin (OSC) was not affected, indicating that their differentiation abilities remained intact, which are crucial parameters for hDPSCs as cell-therapy candidates. These results demonstrated that the new cryopreservation method is low-cost and effective for the good preservation of hDPSCs without compromising cell performance, and can provide ideas and evidence for the future application of stem-cell therapies and the establishment of dental banks.
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Veldheer, Susan, Christina Scartozzi, Amy Knehans, Tamara Oser, Natasha Sood, Daniel R. George, Andrew Smith, Alicia Cohen, and Renate M. Winkels. "A Systematic Scoping Review of How Healthcare Organizations Are Facilitating Access to Fruits and Vegetables in Their Patient Populations." Journal of Nutrition 150, no. 11 (August 28, 2020): 2859–73. http://dx.doi.org/10.1093/jn/nxaa209.
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ABSTRACT Background There is compelling evidence on the impact of diet as preventative medicine, and with rising health care costs healthcare organizations are attempting to identify interventions to improve patient health outcomes. Objectives The purpose of this systematic scoping review was to characterize existing healthcare organization–based interventions to improve access to fruits and vegetables (F&V) for their patient populations. In addition, we aimed to review the impact of identified interventions on dietary intake and health outcomes. Methods Titles and abstracts were searched in PubMed® (MEDLINE®), Embase®, CINAHL®, and the Cochrane Library® from 1 January 1990 to 31 December 2019. To be selected for inclusion, original studies must have included a healthcare organization and have had a programmatic focus on increasing access to or providing fresh F&V to patients in an outpatient, naturalistic setting. The Effective Public Health Practice Project tool was used to assess study quality in 6 domains (selection bias, study design, confounders, blinding, data collection methods, and withdrawals and dropouts). Results A total of 8876 abstracts were screened, yielding 44 manuscripts or abstracts from 27 programs. Six program models were identified: 1) a cash-back rebate program, 2) F&V voucher programs, 3) garden-based programs, 4) subsidized food box programs, 5) home-delivery meal programs, and 6) collaborative food pantry–clinical programs. Only 6 of 27 studies included a control group. The overall quality of the studies was weak due to participant selection bias and incomplete reporting on data collection tools, confounders, and dropouts. Given the heterogeneity of outcomes measured and weak study quality, conclusions regarding dietary and health-related outcomes were limited. Conclusions Healthcare-based initiatives to improve patient access to F&V are novel and have promise. However, future studies will need rigorous study designs and validated data collection tools, particularly related to dietary intake, to better determine the effect of these interventions on health-related outcomes.
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Yang, Shuo, Jessica K. Altman, Sheila Prachand, Austin Tom, Bo Ding, Brent Wu, Leonidas C. Platanias, and Leo I. Gordon. "The Diterpenoid Lactone Andrographolide Induces Reactive Oxygen Species (ROS) Dependent Apoptosis in ATRA Sensitive and Resistant APL Cell Lines." Blood 120, no. 21 (November 16, 2012): 2446. http://dx.doi.org/10.1182/blood.v120.21.2446.2446.
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Abstract Abstract 2446 Andrographolide is a crystalline diterpenoid lactone. It consists of an α-alkylidene- g-butyrolactone moiety and three hydroxyls at C-3, C-14 and C-19, which are responsible for its biological activities. It is the major bioactive ingredient of the medicinal plant Andrographis paniculata and it has been used in Asia for a variety of non-malignant conditions. We previously reported that Andrographolide results in mitochondrial-mediated apoptosis in lymphoma cell lines and fresh malignant cells from patients with lymphoma (Yang et al. Clin Cancer Res 2010:16:4755). Based on the mechanism of action in lymphoma and a prior report in APL (Manikam et al. J Pharm Pharmacol 2009:61:9), we hypothesized that andrographolide may have biological activity in acute promyelocytic leukemia (APL) an that this may be related to reactive oxygen species (ROS). We therefore investigated the effects of andrographolide on cell viability, apoptosis induction, mitochondrial membrane poential and signaling pathways in 3 APL cell lines, the ATRA sensitive line NB4 and the ATRA-resistant lines NB4–007/6 and NB4–306 and 3 samples from patients with APL. Methods: NB4 (ATRA sensitive cell line), NB4–007/6 and NB4–306 (ATRA resistant cell lines) were cultured in RPMI-1640 under standard conditions. Cell viability was measured using the trypan blue or propidium iodide exclusion method. Fresh leukemic cells were obtained from 3 patients after informed consent according to an NU IRB approved protocol. One had ATRA-resistant APL and 2 had de-novo untreated APL. We measured apoptosis by Annexin V-FITC by FACS. We measured mitochondrial membrane potential and cell differentiation by standard techniques. Results: Incubation with increasing concentrations of andrographolide demonstrates loss of cell viability as measured by MTT assay. The IC50 at 48 hours was 6uM for NB4–306, 6.5uM for NB4–007/6 and 9uM for NB4. Apoptosis by Annexin V/FACS demonstrated that at 48 hours there was increasing apoptosis in all 3 cell lines and that the ATRA-resistant cell lines NB4–007/6 and NB4–306 were significantly more sensitive to andrographolide than the ATRA sensitive cell line NB4 (p< 0.025). This was accompanied by PARP and caspase 3-cleavage. There was evidence of decrease in mitochondrial membrane potential, but no effect on differentiation as measured by CD11b expression by flow. We next interrogated signaling pathways and found that in the ATRA resistant line NB4–007/6 there was an increase in phosphorylation of the Forkhead box O transcription factors p-FOXO1 at Thr24 and up-regulation of FasL (which peaked at 6 hours) and p27Kip1. We also demonstrated that andrographolide caused N-acetyl L- cysteine (NAC) reversible down regulation of c-MYC (in the ATRA resistant lines) and p-AKT (T308) (in the ATRA sensitive line) expression. In fresh patient specimens (n=3) there was dose dependent increase in apoptosis at 48 hours (>70% at 10uM, 85% at 20uM). From prior reports and our own data we suspected that the effects of andrographolide were dependent on reactive oxygen species (ROS), and indeed apoptosis was completely inhibited by NAC. Conclusion: Taken together, these data suggest that andrographolide, a novel natural diterpenoid lactone with significant biological activity in cancer, may have activity in patients with ATRA-resistant APL by a mechanism of action that is distinct from ATRA. We believe that these data provide a compelling rationale to add this natural diterpenoid lactone to the clinical trial agenda in APL. Disclosures: No relevant conflicts of interest to declare.
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Whitney, Kaitlyn E., Grant J. Dornan, Jillian King, Jorge Chahla, Thos A. Evans, Marc J. Philippon, Robert F. LaPrade, and Johnny Huard. "The Effect of a Single Freeze–Thaw Cycle on Matrix Metalloproteinases in Different Human Platelet-Rich Plasma Formulations." Biomedicines 9, no. 10 (October 6, 2021): 1403. http://dx.doi.org/10.3390/biomedicines9101403.
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Storing platelet-rich plasma (PRP) for future use is a compelling approach, presuming the retention of biological properties is maintained. However, certain factors in PRP preparations have deleterious effects for the treatment of certain musculoskeletal conditions. The purpose of this study was to measure and compare matrix metalloproteinase protein (MMP) concentrations between fresh and freeze-thawed leukocyte-rich PRP (LR-PRP) inactivated (LR-I) and activated (LR-A) preparations, and leukocyte-poor PRP (LP-PRP) inactivated (LP-I) and activated (LP-A) preparations. A volume of 60 mL of whole blood was drawn from 19 healthy donors. LP-I and LR-I samples were processed using a manual extraction and centrifugation methodology. LP-A and LR-A products were activated with 10% CaCl2 and recombinant thrombin. Blood fractions were either immediately assayed and analyzed or stored at −80 °C for 24, 72 and 160 h. Multiplex immunoassay was used to measure MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, and MMP-12. MMP-1 concentrations increased in LR-A (p < 0.05) and MMP-9 significantly increased in LR-I (p < 0.05), while MMP-2 significantly decreased in LR-I (p < 0.05) and MMP-3 concentrations significantly decreased in LR-A (p < 0.05). MMP-12 concentrations also significantly decreased in LR-I (p < 0.05) from baseline concentrations. There were no significant differences between LP-A and LP-I preparations and MMP concentrations. MMP-10 concentrations in all PRP samples compared to each freezing time point were also not significantly different. MMPs regulate components of the extracellular matrix (ECM) in the remodeling phase of musculoskeletal injury. In this study, we observed a significant increase and decrease in MMP concentrations in response to a single freeze–thaw cycle in inactivated PRP and activated PRP preparations. This evidence contributes to the growing body of literature on the optimization of PRP preparation and storage strategies prior to delivery. Our findings suggest that specific PRP preparations after a single freeze–thaw may be more advantageous for certain musculoskeletal applications based on the presence of MMP concentrations.
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Veldheer, Susan, Christina Scartozzi, Amy Knehans, Tamara Oser, Natasha Sood, Francis Puleo, Joie Cooper, Daniel George, Alicia Cohen, and Renate Winkels. "How Healthcare Organizations Are Facilitating Access to Fruits and Vegetables in Their Patient Populations: A Systematic Scoping Review." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1358. http://dx.doi.org/10.1093/cdn/nzaa059_075.
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Abstract Objectives There is compelling evidence that diet can prevent chronic disease, and with rising health care costs, healthcare organizations are attempting to identify new clinical interventions that can improve the diets of their patients. The purpose of this systematic scoping review was to understand what clinical strategies healthcare organizations are using to increase access to fruits and vegetables (F&V) for their patient populations. In addition, we aimed to review the impact on health outcomes. Methods Titles and abstracts were searched in PubMed® (MEDLINE®), Embase®, CINAHL®, and the Cochrane Library® from January 1, 1990 to December 31, 2019. Original studies must have included a healthcare organization and had a programmatic focus on increasing access to or providing fresh F&V to patients in an outpatient, naturalistic setting. The Effective Public Health Project tool was used to assess study quality in 6 domains (selection bias, study design, confounders, blinding, data collection methods, and withdrawals and dropouts). Two reviewers independently verified included studies, study quality, and data extraction. Results A total of 8877 abstracts were screened which yielded 46 manuscripts from 30 studies. There were 6 program models identified including: 1) cash-back rebate programs, 2) prescription voucher programs, 3) garden-based programs, 4) subsidized food boxes/community supported agriculture (CSA) programs, 5) home-delivery meal programs, and 6) collaborative food pantry-clinical programs. Only 6/30 studies included a control group. The overall quality of the studies was weak due to study participant selection bias, and incomplete reporting on tools used for data collection, confounders, and dropouts. Generally, studies that measured dietary intake found some improvements after these interventions. Other objective health markers such as blood pressure and body mass index had mixed results. Conclusions Healthcare-based models currently being tested that provide patients with access to F&V are novel and appear to have promise. However, future studies will need to use rigorous study designs, validated data collection tools and more sophisticated data analysis methodologies to better determine the effect of these interventions on health outcomes. Funding Sources This study was funded with internal fund to RW and SV.
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Tutt, A., G. T. Stevenson, and M. J. Glennie. "Trispecific F(ab')3 derivatives that use cooperative signaling via the TCR/CD3 complex and CD2 to activate and redirect resting cytotoxic T cells." Journal of Immunology 147, no. 1 (July 1, 1991): 60–69. http://dx.doi.org/10.4049/jimmunol.147.1.60.
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Abstract To investigate whether the retargeting of resting CTL can benefit from cooperative signaling between the TCR/CD3 complex and various accessory molecules, such as CD2, CD4, CD5, and CD8, we have constructed a series of trispecific F(ab')3 derivatives. Each derivative was designed to engage effector T lymphocytes with two Fab' arms, and tumor cells with a single Fab' arm. They were constructed by selective coupling of three mAb Fab' fragments, primarily via their hinge-region sulfhydryl groups, using the cross-linker o-phenylenedimaleimide. En route to the production of trispecific F(ab')3 antibodies a range of bispecific F(ab')2 derivatives was first prepared which could bind simultaneously to two different receptor molecules on T cells. Bispecific derivatives containing specificities for (CD2 (T11(1)) x CD3), (CD3 x CD4), (CD3 x CD8) or two epitopes on CD2, ((T11(1) x (T11(3)), all yielded two to three times the uptake of [3H]thymidine with fresh PBMC to that seen with intact IgG from anti-CD3 (OKT3). The exception to these findings was a bispecific F(ab')2 derivative with specificities for (CD3 x CD5) which caused slightly less proliferation than the control reagent, OKT3 IgG. When these bispecific antibodies were converted into trispecific antibodies (TsAb) by the addition of a Fab' from anti-CD37 they were then all able to retarget resting, unprimed, T cells from fresh PBMC for lysis of CD37+ tumor cells. However, the cytotoxic activity of these reagents fell into two distinct groups: group one, containing (anti-CD3 x anti-CD4 x anti-CD37), (anti-CD3 x anti-CD5 x anti-CD37), and (anti-CD3 x anti-CD8 x anti-CD37), gave minimal lysis and behaved in a similar way to the BsAb, (anti-CD3 x anti-CD37), i.e., no evidence of cooperative signaling for lysis; and group two, containing (anti-T11(1) x anti-CD3 x anti-CD37) and (anti-T11(1) x anti-T11(3) x anti-CD37), which were highly cytotoxic and gave up to 80% specific 51Cr-release. The failure of group one TsAb, in particular (anti-CD3 x anti-CD8 x anti-CD37) which should recruit CD8+ CTL, to give efficient lysis despite having anti-T cell arms that were mitogenic as a bispecific antibody, indicates that the cooperative signaling for proliferation is probably distinct from the signal(s) provided by group two TsAb that activate for both proliferation and lysis.(ABSTRACT TRUNCATED AT 400 WORDS)
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Maes, Gregory E., and Filip A. M. Volckaert. "Challenges for genetic research in European eel management." ICES Journal of Marine Science 64, no. 7 (July 13, 2007): 1463–71. http://dx.doi.org/10.1093/icesjms/fsm108.
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Abstract Maes, G. E., and Volckaert, F. A. M. 2007. Challenges for genetic research in European eel management. – ICES Journal of Marine Science, 64: –. Marine organisms experience a broad range of intrinsic and extrinsic influences during their lives, which impact their population dynamics and genetic structure. Subtle interpopulation differences reflect the continuity of the marine environment, but also pose challenges to those wishing to define management units. The catadromous European eel (Anguilla anguilla) is no exception. Its spawning habitat in the Sargasso Sea and long migration across the North Atlantic qualify it as marine. However, the synergy between hydrographic variability, changing climate, and the impacts of habitat degradation and overfishing in continental waters has negatively affected stock sizes. Its protracted spawning period, variance in age-at-maturity, parental contribution and reproductive success, and the difficulty in sampling the spawning region together may mask a weak geographical genetic differentiation. Recent molecular data report evidence for spatial as well as temporal differences between populations, with the temporal heterogeneity between intra-annual recruitment and annual cohorts exceeding the spatial differences. Despite its common name of “fresh-water eel”, the European eel should really be managed on a North Atlantic scale. The fishery may have to be curtailed, migration routes kept open and water quality restored if it is to survive. Eel aquaculture has to focus on efficient rearing in the short term and controlled breeding in the long term. Future research on eel genetics should focus on (i) sampling and analysing spawning populations and recruitment waves to detect spatio-temporally discrete groups, and establishing a biological baseline from pre-decline historical collections for critical long-term monitoring and modelling of its genetic composition; (ii) the analysis of adaptive genetic polymorphism (genes under selection) to detect adaptive divergence between populations, perhaps requiring separate management strategies; and (iii) improving artificial reproduction to protect natural stocks from heavy exploitation, especially now the species has been categorized as endangered.
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Longo, Pablo G., Luca Laurenti, Stefania Gobessi, Simona Sica, Giuseppe Leone, and Dimitar G. Efremov. "The Akt/Mcl-1 Pathway Plays a Prominent Role in Mediating Pro-Survival Signals Derived from the B-Cell Receptor in Chronic Lymphocytic Leukemia B-Cells." Blood 110, no. 11 (November 16, 2007): 341. http://dx.doi.org/10.1182/blood.v110.11.341.341.
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Abstract Studies of the immunoglobulin variable region gene repertoire have provided compelling evidence that antigen-stimulation through the B-cell receptor (BCR) plays a crucial role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). In addition, previous studies from our lab have shown that CLL B-cells become more resistant to spontaneous and chemotherapy-induced apoptosis following sustained engagement of the BCR with immobilized anti-IgM antibodies, which mimic stimulation with membrane-bound antigens. Investigation of downstream signaling pathways revealed that sustained BCR engagement induces prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the role of sustained activation of the Akt and ERK kinases in regulating CLL growth and survival, we transfected constitutively active mutants of Akt (myr.Akt) and MEK2 in primary leukemic cells and evaluated changes in the expression of relevant apoptosis- and cell-cycle regulatory proteins. Introduction of constitutively active MEK2 resulted in activation of ERK, but did not induce significant changes in the levels of most investigated proteins (Bcl-2, Bcl-xL, Bim, Bax or Mcl-1). The only exception was the inhibitor of apoptosis protein XIAP, which showed increased expression in most but not all experiments. In contrast, transfection of myr.Akt showed a consistent increase in the levels of the antiapoptotic protein Mcl-1, which ranged from 1.5 to more than 4-fold higher levels with respect to cells transfected with control vectors. Increased expression of Mcl-1 was observed in all experiments and paralleled the rise in Mcl-1 that occurred following stimulation of CLL B-cells with immobilized anti-IgM antibodies. The increase in Mcl-1 protein levels was entirely due to post-transcriptional mechanisms, since quantification by real-time PCR did not show an increase in Mcl-1 mRNA levels. Constitutively active Akt also upregulated Bcl-xL and XIAP, although this increase was lower than the increase in Mcl-1. In addition, CLL cells transfected with myr.Akt showed induction of cyclin D3 and an increase in cell size and viability, indicating that sustained activation of Akt is required for both leukemic cell survival and cell cycle progression. To determine the relative importance of Mcl-1, Bcl-xL and XIAP in CLL B-cell survival, we downregulated expression of these proteins in primary CLL B-cells by RNA interference. Surprisingly, downregulation of Bcl-xL and XIAP had no effect on CLL B-cell survival. In contrast, silencing of Mcl-1 induced rapid and potent apoptosis in all investigated cases and abrogated the prosurvival effect of stimulation with immobilized anti-IgM antibodies. Together, these data provide direct evidence that pro-survival BCR signaling in CLL B-cells is mediated, at least in part, through the Akt/Mcl-1 pathway. In addition, they suggest that Mcl-1 could be an attractive candidate for targeting, either with small molecule inhibitors or with pharmacological agents that interfere with BCR signals propagated by the Akt kinase.
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Harriman, R., A. W. Watt, A. E. G. Christie, P. Collen, D. W. Moore, A. G. McCartney, E. M. Taylor, and J. Watson. "Interpretation of trends in acidic deposition and surface water chemistry in Scotland during the past three decades." Hydrology and Earth System Sciences 5, no. 3 (September 30, 2001): 407–20. http://dx.doi.org/10.5194/hess-5-407-2001.
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Abstract. Trends in major ionic components of bulk precipitation were analysed for two sites, Faskally and Loch Ard forest in Scotland, for the period 1972-2000. The pattern of change was not linear. Large reductions in sulphur deposition occurred in the early 1980s and, to a lesser extent, during 1995-2000, with a period of relative stability between 1988-95. pH increased significantly at both sites but nitrate and ammonia only increased significantly at Loch Ard forest. Long-term chemical data from a total of 37 streams and lochs in four selected regions of Scotland were analysed over three time periods (all available data (mostly 1978-2000), 1988-98 and 1995-2000) to match the deposition patterns. For the whole study period a significant decline in non-marine sulphate was found at all sites while the most consistent increases in pH and alkalinity were recorded at all the high elevation loch sites in the Galloway area. Significant reductions in toxic forms of aluminium were also recorded, mostly at sites where pH had increased. Nitrate trends were equivocal except for catchments with clear-felling operations. For these sites, negative trends were found where felling occurred in the 1980s, while positive trends were found at sites with felling in the 1990s. With the exception of one site, dissolved organic carbon concentrations increased significantly with moorland sites showing smaller increases than forested sites. Associated with this change was a significant increase in complexed forms of aluminium. Trends for the 1988-98 period were much smaller than those for the whole study period and in many cases were insignificant. This contrasts with the 1995-2000 period when large and significant reductions in sulphate and nitrate were recorded along with increases in marine salts, probably as a result of climatically related events. Qualitative, experimental and monitoring data from lochs in the Galloway area revealed evidence of recovery of fish populations. Interpretation of chemical and biological trends was clearly influenced by the choice of the time series, especially in relation to deposition and climatic changes. Nevertheless, all the fresh waters included in this study are currently in the best ecological condition since the 1970s in the context of recovery from acidification. Keywords: deposition, trends, acidification, forestry, recovery, fish, climate
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Keady, T. W. J., C. S. Mayne, D. A. Fitzpatrick, and M. Marsden. "The effects of energy source and level of digestible undegradable protein in concentrates on silage intake and performance of lactating dairy cows offered a range of grass silages." Animal Science 68, no. 4 (June 1999): 763–77. http://dx.doi.org/10.1017/s1357729800050797.
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AbstractThe effects of energy source and level of digestible undegraded protein (DUP) in concentrates on silage intake and performance of lactating dairy cows, offered one of a range of grass silages differing in digestibility and intake characteristics, were evaluated in a partially balanced change-over design experiment involving 48 cows. Four silages were prepared using differing management practices prior to and during ensiling. All silages were treated with an inoculant additive. For silages A, В, С and D, dry matter (DM) concentrations were 199, 320, 313 and 223 (s.e. 4.6) g/kg, pH values 3.82, 4.03, 4·03 and 5·27 (s.e. 0.056), ammonia nitrogen (N) concentrations 58, 122, 66 and 356 (s.e. 13.2) g/kg total N and in vivo DM apparent digestibilities 077, 0.75 , 0.60 and 0.60 (s.e. 0·013) respectively. When offered as the sole diet to 12 dairy cows in a partially balanced change-over design experiment, silage DM intakes were 14.7, 14.7, 12.7 and 10.5 (s.e. 0·36) kg/day respectively for silages А, В, С and D. Six concentrates containing three starch concentrations, each at two levels of DUP, were formulated to have similar concentrations of crude protein, metabolizable energy (ME) and fermentable ME. For the low and high starch concentrates and low and high levels of DUP, starch concentrations were 22·5 and 273 g/kg DM and DUP levels were 44 and 60 g/kg DM respectively. Silages were offered ad libitum supplemented with 10 kg fresh concentrate per head per day. For silages А, В, С and D, DM intakes were 10.8, 11.2, 10·7 and 9·1 (s.e. 0·26) kg/day and milk yields 29.0, 27.6, 27.1 and 25.7 (s.e. 0.69) kg/day respectively. With the exception of milk protein concentration there were no significant (P> 0.05) silage type by concentrate energy source and/or level of DUP interactions on silage intake, milk output or composition. Concentrate energy source had no effect (P> 0.05) on silage DM intake, the yields of milk, fat, protein or fat plus protein or milk fat concentration. However, increasing starch concentration increased milk protein concentration (P< 0·001), urinary allantoin concentration (P< 0·01) and diet apparent digestibility (P< 0·001). Altering concentrate DUP level had no effect (P> 0·05) on silage DM intake, yields of milk, protein, fat or fat plus protein, milk f at concentrations or diet apparent digestibility. Increasing the level of DUP decreased milk protein (P< 0·05) concentration. It is concluded that with silages of varying digestibility, fermentation and intake characteristics, there were no concentrate energy source and/or level of DUP by silage type interactions on silage intake, milk yield or composition, or diet apparent digestibility with the exception of a silage type by concentrate level of DUP interaction on milk protein concentration. With out-of-parlour feeding of concentrates the results of the present study suggest that there is no evidence to justify the formulation of concentrates differing in energy source or level of DUP to complement individual silage types.
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Evans, Andrew G., Janice M. Spence, Stephen A. Spence, Paul G. Rothberg, and Richard Burack. "Diffuse Large B-Cell Lymphoma Lacking Surface B-Cell Receptor Expression Are Germinal Center B-Cell (GCB)-Type and Lack Evidence of Known Downstream Activating Mutations." Blood 126, no. 23 (December 3, 2015): 1453. http://dx.doi.org/10.1182/blood.v126.23.1453.1453.
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Abstract Background: Diffuse large B-cell lymphoma (DLBCL) typically express monotypic surface immunoglobulin (sIg) light chain as part of the B-cell receptor (BCR) complex. Occasional cases are, however, sIg-negative and the clinical significance of this remains unclear. Distinct subtypes of DLBCL, including germinal center B-cell-like (GCB) and activated B-cell (ABC) type, exhibit differential dependence upon BCR-mediated survival signals. The role of activating mutations downstream of the BCR signaling complex (i.e. CD79A/B or CARD11), or in parallel costimulatory pathways (i.e. MYD88 mutations), are now well recognized in promoting such survival mechanisms. Surprisingly, however, less is known about the importance of sIg expression, or lack thereof, on various subsets of DLBCL or other aggressive large B cell lymphomas. Design: We sought to further characterize the clinicopathologic and genetic features of primary human surface Ig-negative DLBCL-not otherwise specified (NOS). All cases of large B-cell lymphoma that had flow cytometry performed at the University of Rochester from 2010-2013 were screened for evidence of a surface Ig-negative B-cell population. Additional available immunophenotypic data and/or clinicopathologic features were recorded. PCR heteroduplex analysis and sequencing of fresh frozen tumor samples was performed to identify putative compensatory activating mutations in MYD88 and CD79A /B, respectively. In addition, using multiplexed PCR and sequencing analysis we attempted to identify the presence or absence of functional immunoglobulin heavy chain (IGH)gene rearrangements. Results: Among 209 diagnostic specimens analyzed, 13 cases (6.2%) were found to contain a discrete population of CD19/CD20-positive B-cells lacking sIg light chain expression. These included 8 DLBCL-NOS, nearly all of which were GCB-type, including 6 out of 7 cases, or 83%, which were CD10-positive. This proportion is significantly greater than the 42% of all DLBCL-NOS that express CD10 (based on data from a large publicly available on-line database; p < 0.025, based on binomial probability). Furthermore, of the other high grade sIg-negative B cell lymphomas identified, 4 out of 5 were also CD10-positive. These included 2 cases of B-cell lymphoma, unclassifiable (BCL-U), intermediate between DLBCL and Burkitt lymphoma, and 2 cases of transformed follicular lymphoma (FL) - therefore also histologically and immunophenotypically consistent with derivation from a germinal center B-cell. The only exception was a non-GCB primary CNS lymphoma. Among 5 cases of sIg- DLBCL available for analysis, all were negative for the MYD88 L265P activating mutation, while only a single case contained an activating mutation in CD79A/B (CD79B Y196 ITAM mutation). In the same set, only 2 (of 5) cases produced amplicons by IGH PCR, and sequencing revealed only one of these had an intact reading frame. Conclusion: DLBCL-NOS lacking definitive sIg light chain expression are infrequent (less than 10%), but these tumors are predominantly GCB subtype. This observation lends support to the model that these tumors rely less on BCR-mediated survival signals, which may have implications for choosing targeted therapy. The mechanism by which these lymphoma survive despite the apparent lack of functional BCR is unknown, but compensatory activating mutations known to be frequent among ABC-type DLBCL appear to be lacking. Disclosures No relevant conflicts of interest to declare.
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Peterson, Julie A., Maria Gitter, Daniel W. Bougie, Shannon Pechauer, Kathleen Hopp, Brad Pietz, Aniko Szabo, Brian R. Curtis, Janice McFarland, and Richard H. Aster. "Role Of Maternal Immunization Against Low Frequency Human Platelet Antigens (LFHPA) In Neonatal Alloimmune Thrombocytopenia (NAIT)." Blood 122, no. 21 (November 15, 2013): 38. http://dx.doi.org/10.1182/blood.v122.21.38.38.
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Abstract Neonatal alloimmune thrombocytopenia (NAIT) is largely caused by maternal immunization against Human Platelet Antigens (HPA) inherited by a fetus from its father. In about 70% of apparent NAIT cases, however, maternal HPA antibodies are not detected by standard serologic testing. At least 24 low frequency HPAs (LFHPA) have now been implicated in NAIT. Fathers are not ordinarily typed for these antigens and the corresponding antibodies can be difficult to detect. We studied paternal and maternal blood samples from suspected NAIT cases to investigate the extent to which maternal immunization against LFHPAs causes “antibody-negative” NAIT. In Phase 1, we studied paternal DNA in 244 NAIT cases not resolved by standard laboratory testing in which there was compelling clinical and/or serologic evidence for NAIT. LFHPAs were identified by full length sequencing of relevant exons encoding platelet glycoproteins (GP). Sixteen LFHPAs (6.6% of cases) were identified. HPA-4b, 6bw, 11bw, 12bw, 13bw, 19bw, 20bw, 21bw, 22bw, and 23bw were found in single cases and HPA-9bw in 6 cases. In 15 of the 16 cases, a maternal antibody reactive with paternal platelets and/or a platelet GP was identified. Cases studied in Phase 1 were highly selected. To obtain an unbiased estimate of the extent to which LFHPAs trigger NAIT, we determined the prevalence of 22 recognized LFHPAs in fathers of 1067 consecutive “antibody-negative” NAIT cases using high throughput screening methods (Phase 2). Mothers of 1338 cases were similarly typed to assess the normal prevalence of LFHPAs in a population racially/ethnically similar to the fathers. Of the 1067 fathers, 28 (2.6%) were positive for a LFHPA. LFHPAs identified were HPA-4b (1 case), 6bw (2), 8bw (1), 9bw (17), 12bw (4) and 21bw (3). Of the 1338 mothers, 27 (2.0%) were positive for a LFHPA. Maternal LFPAs identified were 4b (2 cases), 6bw (5), 9bw (12), 12bw (4), 13bw (3) and 21bw (1). Of the LFHPAs identified, only HPA-9bw was significantly more common in fathers than in mothers (P=0.02). Serologic evaluations done in the Phase 2 cases provided evidence for maternal antibodies against paternal GPIIb/IIIa in only 2 of 23 instances in which the paternal low frequency antigen was located on this GP complex. Findings made in Phase 1, show that efforts to identify a paternal LFHPA in unresolved NAIT cases can be rewarding when maternal serum reacts with paternal platelets and the clinical picture strongly suggests NAIT. The Phase 2 studies of consecutive unresolved NAIT cases show that, with the exception of HPA-9b, the prevalence of LFHPAs is about the same in mothers and fathers of apparent NAIT cases not attributable to maternal immunization against “common” HPAs. It is clear that maternal immunization against an LFHPA can account for only a small fraction of the apparent “diagnostic gap” in serologic diagnosis of NAIT. HPA-9bw is by far the most important immunogen among the recognized LFHPAs and consideration should be given to typing fathers of suspected NAIT cases routinely for this antigen. Recent studies suggest that “low avidity” HPA antibodies not detected using conventional serology may account for an unknown fraction of the “antibody-negative” NAIT cases. Whether HLA antibodies cause NAIT more often than has been thought also deserves re-examination. Disclosures: No relevant conflicts of interest to declare.
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Schröder, Stefan E., Jian-Yang Li, Marc D. Rayman, Steven P. Joy, Carol A. Polanskey, Uri Carsenty, Julie C. Castillo-Rogez, et al. "Ceres’ opposition effect observed by the Dawn framing camera." Astronomy & Astrophysics 620 (December 2018): A201. http://dx.doi.org/10.1051/0004-6361/201833596.
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Context. The surface reflectance of planetary regoliths may increase dramatically towards zero phase angle, a phenomenon known as the opposition effect (OE). Two physical processes that are thought to be the dominant contributors to the brightness surge are shadow hiding (SH) and coherent backscatter (CB). The occurrence of shadow hiding in planetary regoliths is self-evident, but it has proved difficult to unambiguously demonstrate CB from remote sensing observations. One prediction of CB theory is the wavelength dependence of the OE angular width. Aims. The Dawn spacecraft observed the OE on the surface of dwarf planet Ceres. We aim to characterize the OE over the resolved surface, including the bright Cerealia Facula, and to find evidence for SH and/or CB. It is presently not clear if the latter can contribute substantially to the OE for surfaces as dark as that of Ceres. Methods. We analyze images of the Dawn framing camera by means of photometric modeling of the phase curve. Results. We find that the OE of most of the investigated surface has very similar characteristics, with an enhancement factor of 1.4 and a full width at half maximum of 3° (“broad OE”). A notable exception are the fresh ejecta of the Azacca crater, which display a very narrow brightness enhancement that is restricted to phase angles <0.5° (“narrow OE”); suggestively, this is in the range in which CB is thought to dominate. We do not find a wavelength dependence for the width of the broad OE, and lack the data to investigate the dependence for the narrow OE. The prediction of a wavelength-dependent CB width is rather ambiguous, and we suggest that dedicated modeling of the Dawn observations with a physically based theory is necessary to better understand the Ceres OE. The zero-phase observations allow us to determine Ceres’ visible geometric albedo as pV = 0.094 ± 0.005. A comparison with other asteroids suggests that Ceres’ broad OE is typical for an asteroid of its spectral type, with characteristics that are primarily linked to surface albedo. Conclusions. Our analysis suggests that CB may occur on the dark surface of Ceres in a highly localized fashion. While the results are inconclusive, they provide a piece to the puzzle that is the OE of planetary surfaces.
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Citrome, Leslie, James Norton, Kathy Chi-Burris, and George Demos. "152 Pimavanserin for the Treatment of Parkinson’s Disease Psychosis: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed." CNS Spectrums 23, no. 1 (February 2018): 94–95. http://dx.doi.org/10.1017/s1092852918000469.
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AbstractStudy ObjectivePsychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.MethodsNNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.ResultsNNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are <10, and as robust as 4, denoting that PIM is a potentially efficacious intervention. NNH values for tolerability outcomes for PIM 34 mg/d (as well as for doses that range from 8.5 mg/d to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.ConclusionsUsing the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.
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Jobling, S., and C. R. Tyler. "Endocrine disruption in wild freshwater fish." Pure and Applied Chemistry 75, no. 11-12 (January 1, 2003): 2219–34. http://dx.doi.org/10.1351/pac200375112219.
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Endocrine disruption has been reported in freshwater fish populations around the world. This phenomenon ranges from subtle changes in the physiology and sexual behavior of fish to permanently altered sexual differentiation and impairment of fertility. Despite widespread reports of endocrine disruption in fish (and this is well characterized at the individual level), few studies have demonstrated population-level consequences as a result of exposure to endocrine-disrupting chemicals (EDCs). An exception to this is in Lake Ontario Lake trout where precipitous declines in the population have been linked with periods of high exposure to organochlorine chemicals (known EDCs). Recently, it has been established that roach (Rutilus rutilus) exposed to treated sewage effluent (that contains complex mixtures of EDCs) in UK rivers, have a reduced reproductive capacity. This, in turn, may have population-level consequences. Evidence for a link between exposure to effluents from kraft mill (BKME) and sewage treatment works (STWs) and altered reproductive function in freshwater fish is compelling. In most cases, however, a causal link between a specific chemical and a physiological effect has not been established. Indeed, identifying specific chemical(s) responsible for adverse effects observed in the wild is difficult, given that tens of thousands of man-made chemicals enter the aquatic environment and that mixtures of chemicals can have combination (e.g., additive) effects. Some EDCs are known to act at a number of different body targets to affect a variety of physiological processes, further complicating the identification of the causative agent(s). Endocrine disruption appears to be particularly widespread in freshwater fish populations. There is little evidence, however, to suggest fish are more susceptible to EDCs relative to other wildlife. Notwithstanding this, there are some features of the endocrine physiology of fish that may be particularly susceptible to the effects of EDCs, including the processes of sex-determination and smoltification (in salmonids). Furthermore, their aquatic existence means that fish can be bathed constantly in a solution containing pollutants. In addition, uptake of chemicals readily occurs via the gills and skin, as well as via the diet (the major exposure route for most EDCs in terrestrial animals). The exposure of fish early life stages to the cocktail of EDCs present in some aquatic environments may be of particular concern, given that this is an especially vulnerable period in their development. The challenge, from the point of view of ecological risk assessment, is to determine effects of EDCs on freshwater fish populations and freshwater ecosystems. In order to meet this challenge, high-quality data are required on the population biology of freshwater fish, on the effects of EDCs on their various life history characteristics, and comprehensive and appropriate population models. Basic information on the population biology of most species of wild freshwater fish is, however, extremely limited, and needs significant improvement for use in deriving a sound understanding of how EDCs affect fish population sustainability. Notwithstanding this, we need to start to undertake possible/probable predictions of population level effects of EDCs using data derived from the effects found in individual fish. Furthermore, information on the geographical extent of endocrine disruption in freshwater fish is vital for understanding the impact of EDCs in fish populations. This can be derived using published statistical associations between endocrine disruption in individual fish and pollutant concentration in receiving waters. Simplistic population models, based on the effects of EDCs on the reproductive success of individual fish can also used to model the likely population responses to EDCs. Wherever there is sufficient evidence for endocrine disruption in freshwater fish and the need for remediation has been established, then there is a need to focus on how these problems can be alleviated. Where industrial chemicals are identified as causative agents, a practical program of tighter regulation for their discharge and/or a switch to alternative chemicals (which do not act as EDCs) is needed. There are recent examples where such strategies have been adopted, and these have been successful in reducing the impacts of EDCs from point source discharges on freshwater fish. Where EDCs are of natural origin (e.g., sex steroid hormones from human and animal waste), however, remediation is a more difficult task. Regulation of the release of these chemicals can probably be achieved only by improvements in treatment processes and/or the implementation of systems that specifically remove and degrade them before their discharge into the aquatic environment.
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Bird, J., A. M. Idris, D. Rogan, and J. K. Brown. "Introduction of the Exotic Tomato yellow leaf curl virus-Israel in Tomato to Puerto Rico." Plant Disease 85, no. 9 (September 2001): 1028. http://dx.doi.org/10.1094/pdis.2001.85.9.1028b.
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Thirty-five-day-old tomato plants (cultivar Florasette) exhibited yellow leaf curling, stunting, and extremely reduced fruit set in spring 2001, in Guanica, Puerto Rico (PR). Twenty percent disease incidence was observed in this field and, 8 weeks later, 75% of the plants showed symptoms. These symptoms were distinct from those caused by other tomato-infecting begomoviruses reported previously from PR, namely Merremia mosaic virus, Tomato mottle virus (ToMoV), and Potato yellow mosaic virus (1). A colony of the B biotype of Bemisia tabaci (Genn.) was used to transmit the suspect virus from symptomatic plants collected in the field and established in the greenhouse in Rio Piedras, PR. The suspect virus was transmitted readily to tomato cultivar Roma (10 of 10 plants), and symptoms were like those observed in the field. Symptoms also were reminiscent of those described for several Old World begomoviruses, referred to as Tomato yellow leaf curl virus (TYLCV). Total nucleic acids were isolated from three symptomatic field samples and three greenhouse-inoculated tomato plants showing typical disease symptoms. Extracts were analyzed by polymerase chain reaction (PCR) with primers AV2466 and AC1145 to amplify a begomoviral fragment (approximately 1.1 bp) that contains a portion of the intergenic region and the viral coat protein gene (CP) (2). Amplicons were cloned, and their nucleotide sequences were determined. A comparison of CP with other well-studied begomoviral nucleotide sequences revealed that the CP sequences for field isolates 1 to 6 shared 99.7 to 100% identity with each other and 99.9 to 100% identity with TYLCV from Israel (TYLCV-IL; accession no. X76319) as well as TYLCV-IL isolates discovered in the Dominican Republic (DO; accession no. AF024715) and, subsequently, in Florida. TYLCV-specific PCR primers (forward) 5′-GAATTCCGCCTTTAA-TTTG-3′ and (reverse) 5′-GAATTCCCACTATCTTTCTC-3′ were used to amplify the complete viral genome form a PR field isolate. An expected-sized amplicon of approximately 2.8 kb was obtained, and the nucleotide sequence of two cloned amplicons was determined. Genome organization revealed a predicted precoat open reading frame of 351 bp, which is characteristic of other Old World begomoviruses, including TYLCV-IL. Nucleotide comparisons indicated that the PR isolate shared 99% nucleotide sequence identity with TYLCV-IL (first reported from Israel) and introduced TYLCV-IL isolates in DO and Florida, thereby confirming the introduction of TYLCV-IL into PR. TYLCV-IL was first identified several years ago in the Western Hemisphere, and the virus has been reported in five offshore locations and three continental U.S. states since its initial introduction into the DO in the early 1990s. Considering the extreme virulence of TYLCV-IL compared with most New World tomato-infecting begomoviruses, this introduction, which likely occurred from a nearby Caribbean country or Florida, has the potential to destroy the fresh-market tomato industry in PR, which supplies tomatoes to the continental United States during the winter months. There is compelling evidence for the routine movement of tomato seedlings from the continental United States to this location in PR throughout the last 10 years, including the previous introduction of ToMoV (1). These incidences and others indicate the need for those in infected areas to take precautions to avoid further spread of this highly damaging virus in and adjacent to the Caribbean region. References: (1) A. M. Idris et al. Phytopathology 88:S42, 1998. (2) A. M. Idris and J. K. Brown, Phytopathology 88:648, 1998.
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Giuliani, Nicola, Francesca Novara, Katia Todoerti, Nadia Zaffaroni, Raffaella Villa, Paola Storti, Maria Ester Bernardo, et al. "Are the Myeloma Bone Microevironment Cells Tumoral or Not?." Blood 114, no. 22 (November 20, 2009): 1816. http://dx.doi.org/10.1182/blood.v114.22.1816.1816.
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Abstract Abstract 1816 Poster Board I-842 Multiple myeloma (MM) is characterized by a tight relationship between tumor and bone microenvironment cells that supports the survival of MM cells and determines a severe impairment of bone homeostasis. Mesenchymal/osteoblastic cells have a critical pathophysiological role in this process either through the overproduction of growth factors and osteoclastogenic molecules or undergoing them same to alterations responsible of bone formation suppression that rarely repairs even after disease remission. These evidences suggest that bone microenvironments cells could be directly involved in myelomagenesis although it is still unclear whether bone microenvironment cells are primary tumoral in MM patients. To clarify this issue, we analyzed immunophenotypic, functional, transcriptional and genomic profiles of bone-derived mesenchymal (MSC) and osteoblastic (OB) cells obtained from a cohort of 24 MM patients at the diagnosis, 7 MGUS patients and 8 healthy donors (N) underwent to orthopedic surgery. MSC cells were isolated from bone biopsies collected in V-glass tube and minced extensively with surgical scissors. OB cells were directly isolated from the minced bone chips collected at the bottom of V-glass tube. The presence of potential haemopoietic and MM contaminating cells was excluded by FACS analysis in both MCSs and OBs, testing CD3, CD14, CD20 and CD138 antigens as well as the expression of CD105, CD146 and the osteoblast markers osteocalcin, alkaline phosphatase, collagen I and Runx2 evaluated in OBs as compared to MSCs Any significant difference in the immunophenotype of MSCs and OBs was not found between MM, MGUS and N with the exception of Runx2 expression that was found to be lower in MM vs. N-MSCs. Cell proliferation and cell doubling/day were found to be higher in MSCs as compared to OBs even if any significant difference was not found across the three groups analyzed. The transcriptional analysis of isolated MSCs and OBs was performed using high-density GeneChip® oligonucleotide microarrays. A multiclass analysis identified 43 differentially expressed genes, which characterized N-MSCs versus MM-MSCs cases but did not distinguish MGUS and MM samples. The molecular signature showed a modulation of genes involved in cell adhesion, cell cycle, transcriptional regulation (MAF and HOX genes) and cell proliferation. A similar transcriptional pattern (78 differentially expressed genes) was observed in N-OBs versus MM-OBs samples. Interestingly, HOXB genes (HOXB2, HOXB6 and HOXB7) were found to be up-regulated in MM as compared to N OBs. Gene expression profiling data were then confirmed by real time PCR. The genomic profiles of MSCs and OBs, obtained from 10 MM patients, were generated by whole-genome array-comparative genomic hybridization (array-CGH) using the 105K platform with a resolution of about 60 kb. Experiments were performed according to the Agilent's protocol v 5.0. DNA either from CD3+ or PBC cells or saliva of every patient was used as control DNA in all experiments. No chromosomal abnormality was observed in MSCs whereas the presence of chromosomal rearrangements and trisomy were found in the OBs of about 50% of MM patients. These abnormalities were different to those observed in CD138+ MM cells of the same patients and the percentage of OBs carrying these abnormalities increased in the late culture passages. Finally, the presence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomere (ALT) have been investigated in cultures at early passages of MSCs and OBs. TA was determined using the telomeric repeat amplification protocol, a PCR-based method in which telomerase extends a radiolabeled synthetic primer resembling telomeric DNA, in both fresh and frozen MSC and OB cultures obtained from 9 MM and 4 MGUS patients. ALT was detected by assaying ALT-associated promyelocytic leukaemia (PML) nuclear bodies [APB], using a combined technique of PML immunofluorescence and telomere FISH, in fresh MSC and OB cultures obtained from both MM and MGUS patients. Notably, no evidence of TA and ALT expression was found in all the tested cultures of both MSCs and OBs indicating that both cells do not display malignant transformation. Overall, our preliminary data indicate that in MM patients both MSCs and OBs show transcriptional alterations as compare to controls and OBs may share genomic abnormalities although these are unlike to be correlated with a primary tumoral feature. Disclosures No relevant conflicts of interest to declare.
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Koning, Marvyn T., Rudolf Übelhart, Arjen H. G. Cleven, Willem H. Zoutman, Sander A. J. van der Zeeuw, Philip Kluin, Marieke Griffioen, et al. "Antigen-Independent, Autonomous B-Cell Receptor Signaling As a Dominant Candidate Oncogenic Mechanism in ABC DLBCL." Blood 128, no. 22 (December 2, 2016): 778. http://dx.doi.org/10.1182/blood.v128.22.778.778.
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Abstract Background The activated B-cell (ABC) type of diffuse large B-cell lymphoma (DLBCL) is clinically more aggressive than the germinal center (GCB) type. The gene expression profile of ABC DLBCL resembles that of mature B cells upon stimulation via their B-cell receptor (BCR). In app. 10% of ABC DLBCL cases, this signature can be explained by gain-of-function mutations in CARD11. Recent evidence suggests that autoantigen recognition by the BCR sustains the viability of ABC DLBCL in vitro (Young, PNAS 2015), although the functional relationship to CARD11 mutations remains unresolved. Antigen-independent, constitutively active BCR signaling is a fundamental oncogenic mechanism of CLL (Dühren-von Minden, Nature 2012). We therefore explored the hypothesis that autonomous BCR signaling akin to CLL could be operative in ABC DLBCL and would represent an alternative but functionally complementary oncogenic mechanism to activating CARD11 mutations in ABC DLBCL lymphomagenesis. Methods BCR transcripts were identified from archived fresh-frozen biopsies of 14 histologically confirmed, CD10-negative, IgM-expressing DLBCL by ARTISAN PCR, a novel anchored RT-PCR for unbiased isolation of full-length BCR transcripts facilitated by template switching (Koning, BJH 2016). Clonal full-length BCR were identified by single molecule sequencing on the PacBio platform. All biopsies were screened for mutations in CARD11 and CD79 by Sanger sequencing. To test for autonomous BCR signaling activity, murine triple KO (TKO) cells were transduced with functional DLBCL BCR (Dühren-von Minden, Nature 2012). TKO cells lack the rag2 and lambda5 genes and are therefore developmentally arrested at the pre-B-cell stage. In addition, TKO cells have their wild-type SLP65 adaptor replaced with a tamoxifen-dependent SLP65 variant. When transduced with a functional BCR, autonomous or antigen-induced BCR signaling can be measured upon restoring functionality of the BCR signalling cascade with tamoxifen as calcium flux by flow cytometry and robust cellular proliferation. Results Re-examination by immunohistochemistry for CD10, PAX5, MUM1, and Bcl-6 was possible in 12 cases and identified three cases as GCB-type DLBCL. Nine cases were classified as non-GCB DLBCL, including one primary CNS DLBCL and three leg-type primary cutaneous DLBCL (LT DLBCL). One non-GCB DLBCL was found to carry a potentially activating CARD11 M212K mutation (Table). BCR of the three GCB DLBCL served as controls and lacked an autonomous BCR signal. In contrast, TKO cells transduced with five of the seven remaining DLBCL BCR (71%) showed robust calcium flux and proliferation upon activation of SLP65 by tamoxifen without additional BCR crosslinking. In accordance with our hypotheses, the CARD11-mutated non-GCB DLBCL case lacked autonomous BCR signaling. This case and the second, non-GCB DLBCL case lacking autonomous BR activity that carried wild-type CARD11 both expressed a BCR with the IGHV4-34 allele. Unexpectedly, the three LT DLBCL also did not exhibit autonomous BCR signaling. Conclusion Our data demonstrate autonomous BCR activity in a dominant fraction of non-GCB DLBCL. In striking similarity to CLL, these results point to an oncogenic role of a structurally normal BCR in non-GCB DLBCL that does not require binding of external autoantigens. Consistent with our hypotheses, antigen-independent signaling of a structurally normal BCR signaling cascade is a compelling candidate alternative mechanism to activating mutations in signal-transducing components of the BCR pathway. Both mechanisms may therefore induce the characteristic gene expression signature of ABC DLBCL. In addition, this finding readily explains the higher likelihood of ABC DLBCL with wild-type CD79 and CARD11 to respond to BCR signaling inhibition by BTK inhibitors (Wilson, Nat Med 2015). In contrast, LT DLBCL, which otherwise resembles ABC DLBCL, does not exhibit autonomous BCR signaling, suggesting yet another oncogenic mechanism that may explain its dismal prognosis. Finally, the non-GCB DLBCL lacking both autonomous BCR signaling and a potentially activating CARD11 mutation expressed the inherently autoreactive IGHV4-34 allele, opening the possibility that strong autoantigen stimulation might substitute for autonomous BCR signaling activity, thereby offering an alternative explanation for the BCR signaling pathway addiction in IGHV4-34-expressing cases. Table. Table. Disclosures Vermeer: Innate Pharma: Other: Investigator in a clinical trial.
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DeRoin, Lia, Marcela Cavalcante De Andrade Silva, Kristin Petras, Kelly Arndt, Nathaniel Phillips, Pankhuri Wanjari, Hari Prasanna Subramanian, et al. "Assessing the Feasibility and Limitations of Cultured Skin Fibroblasts for Germline Genetic Testing in Hematologic Disorders." Blood 136, Supplement 1 (November 5, 2020): 35–36. http://dx.doi.org/10.1182/blood-2020-138431.
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Introduction Peripheral blood is the standard tissue source for germline genetic testing in most scenarios. In patients with hematologic malignancies, however, peripheral blood frequently contains tumor- or clonal hematopoiesis-related acquired genetic variants, often occurring in genes that can also cause inherited cancer susceptibility if present in the germline. Thus, an alternative tissue source is necessary. Cultured skin fibroblasts have been used as a potentially ideal alternative because they are free from blood contamination and provide ample DNA yields, advantages that other alternatives such as saliva or nail clippings lack. However, optimal culture methods, expected time from biopsy to sufficient DNA yield, culture failure rate, and limitations of this technique, including the possibility of variants being acquired solely due to the culturing process, are not yet known. Methods We conducted a retrospective cohort study of subjects with cytopenias or hematologic malignancies who underwent skin biopsy and fibroblast culture for germline genetic testing from April 2014 to June 2018. Skin biopsy culture technical data, including time from biopsy to culture set-up, shipment from an outside institution, culture failure, and biopsy size, were abstracted from tissue culture logs. Patient demographics, comorbidities, medication history, and hematologic diagnosis and treatment were abstracted from medical records. Next generation sequencing data from targeted capture of 144 inherited cancer and bone marrow failure predisposition genes obtained for clinical genetic testing purposes were analyzed to identify variants at both germline (40-60%) and subclonal (10-40%) variant allele frequencies (VAF). Pathogenicity was interpreted according to ACMG/AMP guidelines. Fisher's exact tests and logistic regression models were used to assess associations with culture failure. T-tests and linear regression models were used to assess factors associated with mean time to confluency. Results In total, we studied 350 samples from unique patients, including 61 (24%) who carried one or more pathogenic or likely pathogenic cancer susceptibility gene variant(s). Overall, 16 of the 350 (5%) biopsies failed to grow in culture. The median time from skin biopsy to sufficient growth to extract DNA for genetic testing was 27 days (IQR 22-29 days). Culture failure was significantly more likely in samples with a delay in culture initiation for 24 hours post biopsy (OR=4.32; p<0.01), and a pathogenic germline variant in a gene associated with telomere maintenance (OR=64.50; p<0.01). Factors associated with an increased mean time to sufficient growth included prior allogeneic stem cell transplant (32.1 days versus 27.2 days; p<0.01) and prior intravenous (IV) steroid exposure (29.9 days versus 26.4 days; p<0.01). Among samples cultured successfully, carriers of any pathogenic germline variant had a significantly decreased mean time to sufficient growth (25.4 days versus 28.6 days; p<0.01). A pathogenic or likely pathogenic subclonal variant was identified in 11 (4%) subjects at a median VAF of 20%. Among eight of these with additional tissue available, the presence of the variant was confirmed in four (50%). In individual cases, we found evidence of loss of a pathogenic variant in the hematopoietic malignancy. In one patient with a pathogenic variant with a 50% VAF in the original skin culture, the variant was not present in a skin culture from a second, fresh skin biopsy done due to discordant phenotype. Conclusions Culturing of skin fibroblasts for germline genetic testing in patients with hematologic disorders has a high success rate, especially when cultures are initiated within 24 hours of collection, and adds on average 27 days to genetic testing turnaround time. From patients with a hereditary syndrome, most skin biopsies will culture with the exception of individuals with a short telomere syndrome. For this subset, a direct skin biopsy without culture may be necessary. Subclonal variants at VAFs relevant to interpretation of a germline test were found in 4% of cases. Half were confirmed in an alternative tissue. Etiology of the subclonal variants, whether acquired during the culturing process or due to mosaicism or sequencing biases was not always clear. Careful assessment of the clinical phenotype in interpreting and applying germline genetic results to patient care will always be warranted. Disclosures Godley: UptoDate, Inc.: Honoraria; Invitae, Inc.: Membership on an entity's Board of Directors or advisory committees. Segal:BMS: Consultancy, Research Funding; AbbVie: Consultancy; Merck: Consultancy; Astra Zeneca: Consultancy. Churpek:UpToDate, Inc: Honoraria.
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Andreasen, Marianne Høyem. "Agerbruget i enkeltgravskultur – Senneolitikum og ældre bronzealder i Jylland belyst ud fra plantemakrofossil." Kuml 58, no. 58 (October 18, 2009): 9–55. http://dx.doi.org/10.7146/kuml.v58i58.26388.
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Agriculture in Jutland during the Single Grave culture, Late Neolithic and Early Bronze Age – as revealed by archaeobotanical analysesPlant macrofossils can, together with other archaeological finds, provide an insight into many aspects of past agriculture and society. They can be preserved in various ways (fig. 1).Carbonised plant macro-remains can give us information on some of the species handled and used by people in the past, but they do not provide a complete picture of the exploited flora as not all plants have an equal chance of becoming charred. To aid analysis of charred plant macrofossils, soil samples are often processed in a socalled flotation machine (fig. 2).Waterlogged plant macrofossils can provide a view of the vegetation around a particular site, but it can be difficult to determine which plants people exploited in the past and which simply occurred naturally. Waterlogged plant macrofossils are prepared for analysis by wet-sieving.The other forms of preservation (fig. 1) give only a very fragmented picture of the past flora as very special conditions lead to their preservation.The period extending from the Single Grave culture to the end of the Early Bronze Age covers about 1800 years of Danish prehistory (2800-1800 BC). To date, a total of 41 archaeobotanical analyses have been carried out from 35 sites from this period in Jutland (fig. 3), which provides a relatively poor chronological representativity. Seen geographically, there are many blank areas and other areas show a tendency towards a clustering of sites (fig. 3). This distribution is not an expression of the distribution of the prehistoric evidence but is exclusively a result of a bias in sampling.Arable agriculture was introduced to Southern Scandinavia around 4000 BC, and during the Funnel Beaker culture it was dominated by emmer, although naked barley, hulled barley, einkorn and bread wheat were also present from the beginning. Naked barley did, however, become more common during the course of the period towards the beginning of the Single Grave culture (fig. 4). At the same time, pollen evidence reveals that there was a general opening up of the landscape with a greater extent of grazing land and arable fields, the exception to this being in Djursland.During the Single Grave culture naked barley was the dominant crop (fig. 5), but not to such a great extent as was previously thought, becaurse wheat, in the form of emmer (fig. 7), also occurs in such quantities that it must have been a separately cultivated crop. This crop apparently having had a ritual significance, perhaps because it was used in beer making, can perhaps explain the dominant position of naked barley. This ritual element is also apparent in that naked barley was apparently used as a decorative element on certain pottery vessels (fig. 6).In the Late Neolithic, naked barley was no longer the clearly dominant crop (fig. 8), although it does dominate percentagewise with regard to the number of grains and chaff fragments (fig. 9), as wheat is now the dominant crop at seven out of the 13 sites. Naked barley was the dominant form of barley (fig. 10), while emmer was the predominant form of wheat, although there is also a large quantity of spelt in the material, and it is almost the numerical equivalent of emmer (fig. 11). The fact that wheat and barley became more-or-less of equal importance as crops is an interesting development. This suggests that, in the Late Neolithic, there was the adoption of more diverse agriculture in which a greater number of different crops were cultivated than previously. It also seems that several different cereals were cultivated at the same time at most sites. This was an important innovation as it reduced the risk of a total harvest failure.This development continued into the Early Bronze Age, when wheat became increasingly widespread at the cost of barley; various forms of wheat are dominant at seven out of 11 localities (fig. 12). Wheat is also now the dominant cereal type with 56% of all grains and chaff fragments. Naked barley was still the dominant form of barley, but hulled barley occurs at seven localities (fig. 13). With regard to wheat, it varies from locality to locality as to which type is dominant; emmer and spelt are each dominant at two sites and bread wheat is dominant at one (fig. 14). Overall, emmer dominates with 64% of all the identifiable wheat grains and chaff fragments, whereas spelt comprises 24% and the other wheat types are much less widespread (fig. 15). Agriculture in the Early Bronze Age was apparently very diverse, involving the cultivation of many different crops. At least two different crops were cultivated at all sites, probably to spread the risk of crop failure and to secure a good harvest.On the basis of the plant macrofossils and the other archaeological finds it is possible to gain an insight into various agrarian processes. There are no finds of the actual fields, but ard marks have been found dating all the way back to the beginning of the Funnel Beaker culture. Each farmstead probably had more than one field as the dominant cereal types were probably cultivated as monocultures. The fields were ploughed with the aid of a ard, probably a “crook ard”, which is the oldest known type in Denmark (fig. 16). The ard was probably drawn by oxen as seen depicted on the Litsleby rock carving (fig. 17). This is confirmed by finds of cattle foot bones from the Middle Neolithic showing characteristic deformities which indicate the exploitation of oxen as draught animals. We do not know when in the year the fields were ploughed but it is very likely that this took place in connection with preparation for sowing, and possibly also after sowing in order to cover the seed corn with soil. It is generally thought that up until the end of the Roman Iron Age all crops were sown in the spring. Based on the evidence from the weed flora, this seems also to have been the case during the period dealt with here. The weed seed assemblages also indicate that the arable fields were not manured or weeded.On the basis of similarities to modern sickles, it is presumed that cereals were harvested using, respectively, blade sickles (Single Grave culture), flat-flaked flint sickles (Late Neolithic and Early Bronze Age) and bronze sickles (Early Bronze Age). However, no wear analyses have been carried out to date on sickles from these periods. In addition, use could have been made of so-called “threshing combs” (fig. 18), as known from the Late Funnel Beaker culture. Seeds of weeds of short stature seen in the Late Neolithic and Early Bronze Age finds suggest that the cereals were harvested low on the straw.There are no records of threshing implements, but finds of threshed but not fully processed/cleaned naked barley from the Single Grave culture at Grydehøj suggest that use was made of flails, sticks or similar. After threshing, the grain was cleaned, a process possibly carried out in the same way as revealed by ethnographic 55 studies (fig. 19). In the finds so far, it was only possible to identify two waste products from cereal processing: the waste from the final hand-cleaning, by which impurities and glumes are removed (the glumes are most easily removed by loosening them from the lightly roasted grain with the aid of a quern or possibly a wooden mortar (fig. 20)), and the waste product arising from sieving naked barley with a fine-meshed sieve.There are three different find categories representing more-or-less fully processed cereal products – stored grain, offerings and material burnt by accident during cooking or roasting. The grain was probably stored in some form of container but unfortunately these are not often preserved. This is probably due to them being made from organic material, as seen at Peterborg Vest near Horsens (Late Neolithic) where the grain was stored in wooden containers, and during the Iron Age, from where there are finds of wooden containers and leather sacks. Pottery vessels are of course another possibility, but from the study period the only example is from Uglviggård. In the Late Neolithic and Early Bronze Age it appears that the grain was, as a rule, stored in the eastern part of the house.It is difficult to evaluate precisely the economic significance of arable agriculture relative to animal husbandry as the archaeological record tends to favour the former whereas pollen evidence gives better information on the latter. This disparity is probably due to prevailing conditions and the potential for preservation, as well as the fact that cereals (apart from rye) belong to a special group of plants that are “cleistogamous” (fig. 21), i.e. the plant’s flowers never open and, as a consequence, no pollen is released. At the present time it is not possible, therefore, to evaluate precisely the relationship between the economic significance of arable agriculture and animal husbandry. Wild plants were also exploited. There is evidence for the gathering of hazelnuts, apples, berries, various weed seeds and acorns.It is possible, on the basis of the finds of charred grain and seeds, combined with other archaeological finds, to obtain a relatively clear picture of the crops, arable agri culture and agrarian practices in the period extending from the Single Grave culture until the end of the Early Bronze Age. The shift that apparently began at the transition from the Late Neolithic – whereby arable agriculture became increasingly diverse, involving the simultaneous cultivation of several crops at every site - could suggest that arable agriculture became of greater importance relative to animal husbandry and perhaps, in particular, the exploitation of natural resources. At the same time, this strategy distributed risk and therefore provided a more stable subsistence base as the risk of failed crops was reduced. It is possible that this increased stability in the subsistence base could have contributed to laying the foundations for some of the increased surplus apparent in Late Neolithic and Early Bronze Age society in the form of greater investment in prestige objects and the potential to support specialised craftsmen.The economy did not of course just comprise arable agriculture. Animal husbandry also played an important role, but the importance of this role relative to arable agriculture is unfortunately not revealed by the finds. Agriculture was supplemented by the gathering of various nuts, fruits, berries and edible plants. In addition, birds, land and marine mammals were hunted, and there was fishing for fresh- and salt-water fish and gathering of shellfish. In other words, there was a broad-based and diverse economy during all three archaeological periods.Marianne Høyem AndreasenMoesgård Museum
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Kim, Youn H., Sean Whittaker, Steven M. Horwitz, Madeleine Duvic, Reinhard Dummer, Julia J. Scarisbrick, Pietro Quaglino, et al. "Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study." Blood 128, no. 22 (December 2, 2016): 182. http://dx.doi.org/10.1182/blood.v128.22.182.182.
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Abstract Background Cutaneous T cell lymphoma (CTCL) is a chronic disease that negatively impacts quality of life (QoL) and, in advanced stages, has poor prognosis. Current systemic therapies rarely provide reliable and durable responses, and to date, no systemic agent has shown outcomes superior to standard-of-care therapy such as methotrexate (MTX) or bexarotene (Bex). CD30-directed antibody-drug conjugate brentuximab vedotin (BV) has demonstrated marked clinical activity in two phase 2 single-arm trials in CTCL with overall response rates (ORR) of about 70%. These results led to ALCANZA, a randomized, open-label, multicenter phase 3 trial of the efficacy and safety of BV vs physician's choice (PC) of MTX or Bex, in previously treated patients with CD30-expressing CTCL (NCT01578499). This is the first reported randomized phase 3 trial testing a new agent against standard-of-care therapy in CTCL. Methods Adults with CD30-expressing (≥10% of infiltrate by central review) mycosis fungoides (MF) who received ≥1 prior systemic therapy or primary cutaneous anaplastic large cell lymphoma (pcALCL) who received ≥1 prior systemic therapy or radiotherapy were enrolled. Patients were stratified by diagnosis and randomized 1:1 to receive BV 1.8 mg/kg IV, once every 3 weeks, or PC of either MTX 5-50 mg PO, once weekly, or Bex 300 mg/m² (target dose) PO, once daily, for up to 16 three-week cycles, until disease progression or unacceptable toxicity. Primary endpoint was ORR4, defined as ORR lasting ≥4 months, an endpoint that captures response rate and duration as a single measurement. ORR4 was determined by independent review of global response using the ISCL/EORTC consensus guidelines. Global response is a composite of skin evaluation (modified severity weighted assessment tool), radiographic assessment, and Sézary cell enumeration. Key secondary endpoints were CR rate, PFS, and symptom burden measured by the symptom domain of the Skindex-29 QoL tool. Sample size was calculated to provide 90% power to detect a 30% improvement in ORR4. Treatment-emergent adverse events (AEs) were evaluated according to NCI CTCAE v4.03. Results 131 patients were randomized with 128 patients in the intent-to-treat population (97 MF, 31 pcALCL; 3 excluded for insufficient CD30 expression) and assigned to BV (n=64) or PC (n=64). Baseline characteristics were generally balanced between arms with the exception of more patients with extracutaneous disease in the BV arm (Table). In BV vs PC arms, respectively, median age was 62 (22-83) vs 58 (22-83) years; ECOG performance status 0-1 was 95% vs 97%. Patients in each arm had a median of 2 prior systemic therapies. At a median follow-up of 17.5 months, ORR4 (primary endpoint) and PFS strongly favored BV vs PC with ORR4 of 56% vs 13% (p<0.0001) and median PFS of 16.7 vs 3.5 months (HR 0.270; 95% CI, 0.169-0.430; p<0.0001), respectively (Fig 1, 2). ORR was 67% (n=43) with CR 16% for BV, compared with ORR of 20% (n=13) with CR 2% for PC (ORR, p<0.0001; CR, p=0.0046). Skindex-29 showed significantly greater symptom reduction for BV compared with PC (-27.96 vs -8.62; p<0.0001). Patients received a median of 12 (1-16) cycles of BV vs 5.5 (1-16) Bex and 3 (1-16) cycles of MTX. Grade 3-4 AEs, all cause / drug-related, were seen in 41% / 29% with BV vs 47% / 29% with PC. Serious AEs were seen in 29% of patients in each arm. Peripheral neuropathy (PN), any grade, was seen in 67% in the BV arm (32% grade 2, 9% grade 3) and 6% in the PC arm. At last follow-up, 36/44 (82%) patients in the BV arm had improvement or resolution of PN. Discontinuation due to AEs occurred in 24% (BV) vs 8% (PC). Four deaths in the BV arm (3 unrelated to study drug) occurred within 30 days of the last dose. Other AEs were consistent with reported safety profiles for the individual agents. Conclusions In this first report of a randomized phase 3 trial evaluating a new agent vs standard-of-care options in CTCL, the clinical outcome of BV was far superior to PC (MTX or Bex). Highly statistically significant improvements in ORR4 (44%) and median PFS (13.2 months) were observed with BV. Greater ORR with higher CR rate and reduction in symptoms per Skindex-29 symptom domain were also observed in the BV arm. Safety data for BV were consistent with the established tolerability profile. The data from this randomized trial provide compelling evidence favoring BV over PC of Bex or MTX in CD30-expressing CTCL. Disclosures Kim: Kyowa Kirin Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; miRagen: Research Funding; Merck: Research Funding; Soligenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Innate: Research Funding; Portola: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding. Whittaker:Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Other: Investigator in a clinical trial; Seattle Genetics: Other: Investigator in a clinical trial; Galderma: Research Funding. Horwitz:ADCT Therapeutics: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Takeda: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy. Dummer:Allos: Research Funding; Shape: Research Funding; Jonathan Wood & Assoc: Speakers Bureau; Soligenetics: Research Funding; Cell Medica: Consultancy, Honoraria; Therakos: Speakers Bureau; Mallinckrodt Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Covance Laboratory Services: Consultancy; Oncoceuticals: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huya: Consultancy; Eisai: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scarisbrick:Millennium: Consultancy; 4SC: Consultancy. Zinzani:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Wang:Seattle Genetics: Employment, Equity Ownership. Palanca-Wessels:Seattle Genetics: Employment, Equity Ownership. Zagadailov:Takeda Pharmaceuticals: Employment, Equity Ownership; Amerisource Bergen: Equity Ownership. Trepicchio:Takeda Pharmaceuticals: Employment. Liu:Takeda Pharmaceuticals: Employment, Equity Ownership. Little:Takeda Pharmaceuticals: Employment, Equity Ownership.
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D. PAKULSKA, Daria, and Renata Soćko. "Wood dust – aspiration fraction Documentation of proposed values of occupational exposure limits (OELs)." Podstawy i Metody Oceny Środowiska Pracy 33, no. 3(93) (September 10, 2017): 17–90. http://dx.doi.org/10.5604/01.3001.0010.4272.
Full textAbstract:
Wood is the raw material of the wood industry, which is used in the form of solid wood or in the processed form. Occupational exposure to wood dusts occur during processing and woodworking. The highest levels of wood dust concentrations in the work environment were recorded in the furniture and carpentry industries. The number of workers exposed to wood dust in Poland estimated during WOODEX project (2000-2003) amounted to 310 000, of which 79 000 workers were exposed to wood dust at concentrations < 0.5 mg/m3, 52 000 workers at concentrations: 0.5 ÷ 1 mg/m3, 63 000 workers at concentrations: 1 ÷ 2 mg/m3, 72 000 workers at concentrations: 2 ÷ 5 mg/m3 and 44 000 workers at concentrations > 5 mg/m3. According to data from selected sectors of the economy in Poland in the years 2001-2005, developed in collaboration with the Chief Sanitary Inspectorate at the Institute of Occupational Medicine in Łódź, the arithmetic mean value of inhaled wood dust concentrations in the wood and wood products sector (excluding furniture) was 2,08 mg/m3. This concentration was calculated on the basis of 8 602 measurements. In the case of hardwood dust, exceeded values of NDS at worksites were reported in more than 20% of the measurements, whereas in case of softwood – in less than 10% of measurements. Exposure to hardwood dust (mainly oak and beech wood) or in mixture with conifer species (softwood) is correlated with nasopharyngeal adenocarcinomas, whereas non-neoplastic respiratory symptoms, excluding asthma, are not correlated with the specific type of wood. Occupational asthma is most often the result of action of the biologically active compounds present in some wood species (both hardwood and softwood). One of the better-known species of wood and source of knowledge about occupational asthma is the dust of red cedar wood. Both dust hardwood and softwood may impair clear airway, resulting in chronic lung disease. The health effects of exposure to wood dust concern the upper or lower respiratory tract depending on the size of the wood particles. Occupational exposure to wood dust causes: chronic bronchitis, rhinitis and conjunctivitis and skin irritation, also allergic skin reactions. Spirometry has shown the reduction of the lung function index as a result of mechanical or chemical irritation of the lung tissue. It should be noted that changes in pulmonary function and the occurrence of occupational asthma was found in the woodworking industry workers, mainly employed in furniture industry (with no history of atopy) at concentrations below 1 mg / m3 of wood dust. A review of the studies in humans and in experimental animals show that wood dusts exhibit mutagenic and genotoxic effects. Analysis of DNA taken from people with cancer of the paranasal sinuses, employed in exposure to wood dusts showed mutations, mainly in the gene k-ras, which is one of the most frequently activated oncogenes in human cancers. Furthermore, h-ras mutations in adenocarcinoma patients, chromosomal aberrations in carpenter peripheral blood lymphocytes, damage to DNA strands in rats' hepatocytes, increase in micronuclear frequency in cells of mouse intestine and rats' nasal epithelium have been found. Based on results of epidemiological studies, including case-control studies showed the relationship between the incidence of the nose and paranasal sinuses cancer and the exposure to the wood dust. The risk of adenocarcinoma was a significantly higher compared to the risk of squamous cell carcinoma. The International Agency for Research on Cancer concluded that there was sufficient evidence of carcinogenicity of wood dust in humans and assigned them to Group 1 - a substances with proven carcinogenic effects in humans. The Commission of the European Union has included works related to exposure to hard and mixed wood dusts to technological processes classified as carcinogenic to humans (Directive 2004/37 / EC) and has established a BOELV value for the inhalable wood dust fraction on a level of 5 mg/m3 indicating that if there is a mixture of hardwood dust with other wood dusts then NDS refers to the total wood dust present in the mixture. SCOEL Scientific Committee resigned from the division into hard and soft wood and proposed the exposure limit value for wood dust, taking into account not only its irritating effects on upper and lower respiratory tract but also carcinogenicity (inhalable fraction: 1 mg/m3, total dust 0.5 mg/m3). The health effects of exposure to wood dust and the socio-economic conditions have alsobeen considered by the Committee on Safety and Health at Work (ACSHW), which has proposed a BOELV value for hard wood dusts of 3 mg/m3, taking into account that the lower value would result in the closure of many companies, mostly small, employing 1 to 9 employees. Establishment of the hygienic standards of wood dust is complicated by the fact that we never expose to the wood dust itself. At the same time, we are exposed to naturally occurring chemicals in wood (most of them are irritating and sensitizing). In addition, the biological fraction (bacteria, mold) found in wood dust, mainly fresh, as well as wood preservatives such as organic solvents or formaldehyde, increase the health risk. Another variable considered when assessing risk associated with exposure to wood dust is the particle size emitted during wood processing, which varies according to the type of wood and its treatment. Aerodynamic diameter of the particles is generally in the range of 10 to 30 m, which classifies them into an extra thoracic fraction (penetrating head area) or thoracic fraction (penetrating the trachea bronchial area). Percentage of respirable fraction is usually 15 ÷ 20%. When setting the NDS value for wood dusts, data from a cross-sectional survey of 161 people employed in wood dust exposure in 54 furniture companies were used. Nasal patency was examined after exposure to mixed wood dust at a low concentration (0.17 ÷ 0.74 mg/m3), mean (0.74 ÷ 1.42 mg/m3) and high (1.42 mg/m3). With regard to nasal patency before commencement of the work, exposure to medium and high concentration of wood dust significantly increased nasal congestion, reduced nasal cavity capacity and reduced nasal cross-sectional area as a result of 4-7 hours exposure. There was a statistically significant relationship between the concentration of wood dust and the nasal obstruction grade determined by the method of acoustic rhinometry and the subjective assessment. These symptoms also occurred when the dust concentrations were small, but these symptoms were not statistically significant. Furthermore, patients in the control group had significant differences in nasal passivity before commencement of work compared to the post-work period, thus undermining the observed changes at low concentrations (0.17 ÷ 0.74 mg/m3) of wood dust. Taking into account the above data as well as socioeconomic factors discussed with wood industry representatives in Poland, the Interdepartmental Commission on NDS and NDN at its 84th meeting on 4 November 2016 adopted a concentration of 3 mg/m3 for the maximum permissible concentration (NDS) for the inhalable fraction of all wood dust. Socioeconomic considerations were also taken into account in determining the BOELV value for the inhalable wood dust fraction (3 mg/m3) in the European Union. The adoption of this value without distinction for hard and soft wood is a compromise between current NDS values for wood dust with the exception of dust oak and beech (4 mg/m3) and beech and oak dust (2 mg/m3). The proposed value of NDS is at the level proposed by the European Commission for BOELV for the hard wood dust inhalable fraction (3 mg/m3), which takes into account socio-economic conditions of enterprises. Due to the fact that wood dusts have been shown to be carcinogenic, mutagenic and cause pneumoconiosis, the determination of NDSCh values is unjustified. It is proposed to mark the wood dust notation: "Carc. – category 1 carcinogen, according to the classification of the International Agency for Research on Cancer and, by reason of possible sensitization, the letter "A ".