Immunodepletion in xenotransplantation

Xenograft transplantation is perhaps the most immunologically difficult problem in transplantation today. An overwhelming hyperacute rejection reaction (HAR) occurs within minutes of organ implantation. Preformed antibodies are thought to initiate this process. We used a pig-to-dog renal xenograft transplant model and investigated methods of decreasing the severity of hyperacute rejection. Female pigs weighing 15-20 kg were used as donors. Recipients were mongrel dogs weighing 15-25 kg. Experimental dogs were all given a number of treatments of IgG depletion using an antibody removal system (Dupont-Excorim). This machine immunoadsorbs plasma against a column containing immobilized staphylococcal protein A, which is known to bind the IgG Fc receptor. An 84% reduction in the IgG levels and a 71% reduction in IgM levels was achieved. Postoperative assessment was made of urine output, time to onset of HAR, and histopathological examination of the rejected kidneys. Although cross-matches between donor lymphocytes and recipient sera remained strongly positive in the treated dogs, there was a two- to fourfold reduction in the titers. The time to onset of HAR was prolonged in the experimental group, and the urine output was increased slightly. The histopathologic changes in the experimental group generally showed signs of HAR, but of less intensity than in the nonimmunodepleted control group. © 1990 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

Honeybee Colony Vibrational Measurements to Highlight the Brood Cycle

Insect pollination is of great importance to crop production worldwide and honey bees are amongst its chief facilitators. Because of the decline of managed colonies, the use of sensor technology is growing in popularity and it is of interest to develop new methods which can more accurately and less invasively assess honey bee colony status. Our approach is to use accelerometers to measure vibrations in order to provide information on colony activity and development. The accelerometers provide amplitude and frequency information which is recorded every three minutes and analysed for night time only. Vibrational data were validated by comparison to visual inspection data, particularly the brood development. We show a strong correlation between vibrational amplitude data and the brood cycle in the vicinity of the sensor. We have further explored the minimum data that is required, when frequency information is also included, to accurately predict the current point in the brood cycle. Such a technique should enable beekeepers to reduce the frequency with which visual inspections are required, reducing the stress this places on the colony and saving the beekeeper time

Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts

BACKGROUND: The magnitude of the association between Helicobacter pylori and incidence of gastric cancer is unclear. H pylori infection and the circulating antibody response can be lost with development of cancer; thus retrospective studies are subject to bias resulting from classifi- cation of cases as H pylori negative when they were infected in the past. AIMS: To combine data from all case control studies nested within prospective cohorts to assess more reliably the relative risk of gastric cancer associated with H pylori infection.To investigate variation in relative risk by age, sex, cancer type and subsite, and interval between blood sampling and cancer diagnosis. METHODS: Studies were eligible if blood samples for H pylori serology were collected before diagnosis of gastric cancer in cases. Identified published studies and two unpublished studies were included. Individual subject data were obtained for each. Matched odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the association between H pylori and gastric cancer. RESULTS: Twelve studies with 1228 gastric cancer cases were considered. The association with H pylori was restricted to noncardia cancers (OR 3.0; 95% CI 2.3–3.8) and was stronger when blood samples for H pylori serology were collected 10+ years before cancer diagnosis (5.9; 3.4–10.3). H pylori infection was not associated with an altered overall risk of cardia cancer (1.0; 0.7–1.4). CONCLUSIONS: These results suggest that 5.9 is the best estimate of the relative risk of non-cardia cancer associated with H pylori infection and that H pylori does not increase the risk of cardia cancer. They also support the idea that when H pylori status is assessed close to cancer diagnosis, the magnitude of the non-cardia association may be underestimated

Validation of a UPDRS-/MDS-UPDRS-based definition of functional dependency for Parkinson's disease

Copyright © 2020. Published by Elsevier Ltd.Peer reviewedPostprin

Deep Mining of Oxysterols and Cholestenoic Acids in Human Plasma and Cerebrospinal Fluid: Quantification using Isotope Dilution Mass Spectrometry

Both plasma and cerebrospinal fluid (CSF) are rich in cholesterol and its metabolites. Here we describe in detail a methodology for the identification and quantification of multiple sterols including oxysterols and sterol-acids found in these fluids. The method is translatable to any laboratory with access to liquid chromatography – tandem mass spectrometry. The method exploits isotope-dilution mass spectrometry for absolute quantification of target metabolites. The method is applicable for semi-quantification of other sterols for which isotope labelled surrogates are not available and approximate quantification of partially identified sterols. Values are reported for non-esterified sterols in the absence of saponification and total sterols following saponification. In this way absolute quantification data is reported for 17 sterols in the NIST SRM 1950 plasma along with semi-quantitative data for 8 additional sterols and approximate quantification for one further sterol. In a pooled (CSF) sample used for internal quality control, absolute quantification was performed on 10 sterols, semi-quantification on 9 sterols and approximate quantification on a further three partially identified sterols. The value of the method is illustrated by confirming the sterol phenotype of a patient suffering from ACOX2 deficiency, a rare disorder of bile acid biosynthesis, and in a plasma sample from a patient suffering from cerebrotendinous xanthomatosis, where cholesterol 27-hydroxylase is deficient

Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured Porosity Enables Tunable and Sustained Drug Release

In this article we for the first time present a fully synthetic mesoporous geopolymer drug carrier for controlled release of opioids. Nanoparticulate precursor powders with different Al/Si-ratios were synthesized by a sol-gel route and used in the preparation of different geopolymers, which could be structurally tailored by adjusting the Al/Si-ratio and the curing temperatures. In particular, it was shown that the pore sizes of the geopolymers decreased with increasing Al/Si ratio and that completely mesoporous geopolymers could be produced from precursor particles with the Al/Si ratio 2∶1. The mesoporosity was shown to be associated with a sustained and linear in vitro release profile of the opioid oxycodone. A clinically relevant release period of about 12 h was obtained by adjusting the size of the pellets. The easily fabricated and tunable geopolymers presented in this study constitute a novel approach in the development of controlled release formulations, not only for opioids, but whenever the clinical indication is best treated with a constant supply of drugs and when the mechanical stability of the delivery vehicle is crucial

Identification of dissolved organic matter size components in freshwater and marine environments

Dissolved organic matter (DOM) in the transition zone from freshwater to marine systems was analyzed with a new approach for parameterizing the size distribution of organic compounds. We used size-exclusion chromatography for molecular size analysis and quantified colored DOM (CDOM) on samples from two coastal environments in the Baltic Sea (Roskilde Fjord, Denmark and Gulf of Gdansk, Poland). We applied a Gaussian decomposition method to identify peaks from the chromatograms, providing information beyond bulk size properties. This approach complements methods where DOM is separated into size classes with pre-defined filtering cutoffs, or methods where chromatograms are used only to infer average molecular weight. With this decomposition method, we extracted between three and five peaks from each chromatogram and clustered these into three size groups. To test the applicability of our method, we linked our decomposed peaks with salinity, a major environmental driver in the freshwater-marine continuum. Our results show that when moving from freshwater to low-salinity coastal waters, the observed steep decrease of apparent molecular weight is mostly due to loss of the high-molecular-weight fraction (HMW; >2 kDa) of CDOM. Furthermore, most of the CDOM absorbance in freshwater originates from HMW DOM, whereas the absorbing moieties are more equally distributed along the smaller size range (<2 kDa) in marine samples.Peer reviewe

GBA and APOE Impact Cognitive Decline in Parkinson's Disease : A 10-Year Population-Based Study

Acknowledgments: We would like to thank all participants, study personnel from each study, and funders of individual studies and of PICC. We would like to thank Artur Wozniak and Adrian Martin from the University of Aberdeen, Data Management Department, for help in developing the PICC database. We acknowledge the contributions of members of the individual study groups as detailed below. Members of PICC Steering Group: Dr. Angus D. Macleod, Dr. Carl E. Counsell (Chair), University of Aberdeen, UK; Prof. Ole-Bjørn Tysnes, University of Bergen, Norway; Marta Camacho, Dr. Caroline WilliamsGray, University of Cambridge, UK; Dr. Rachael A. Lawson, Newcastle University, UK; Dr. Jodi Maple-Grødem, Prof. Guido Alves, Stavanger University Hospital, Norway; Prof. Lars Forgren, Umeå University, Sweden. CamPaIGN study: Roger A. Barker, Thomas Foltynie, Sarah L. Mason, Caroline H. Williams-Gray. ICICLE-PD Study: David Burn, Lynn Rochester, Alison J. Yarnall, Rachael A. Lawson, Gordon W. Duncan, Tien K. Khoo. NYPUM Study: Lars Forsgren, Jan Linder, Mona Edström, Jörgen Andersson, Linda Eriksson, David Bäckström, Gun-Marie Hariz, Magdalena Domellöf. ParkWest Study: ParkWest Principal investigators: Guido Alves (Norwegian Centre for Movement Disorders, Stavanger University Hospital) and Ole-Bjørn Tysnes (Haukeland University Hospital). Study personnel: Michaela Dreetz Gjerstad, Kenn Freddy Pedersen, Elin Bjelland Forsaa, Veslemøy Hamre Frantzen, Anita Laugaland, Jodi MapleGrødem, Johannes Lange, Karen Simonsen, Eldbjørg Fiske and Ingvild Dalen (Stavanger University Hospital); Bernd Müller, Geir Olve Skeie and Marit Renså (Haukeland University Hospital); Wenche Telstad, Aliaksei Labusau and Jane Kastet (Førde Hospital); Ineke HogenEsch, Marianne Kjerandsen and Liv Kari Håland (Haugesund Hospital); Karen Herlofson, Solgunn Ongre, and Siri Bruun (Sørlandet Hospital Arendal). PICNICS study: Roger A. Barker, Marta Camacho, Gemma Cummins, Jonathan R. Evans, David P. Breen, Ruwani S. Wijeyekoon, Caroline H. Williams-Gray. PINE Study: Medical: Carl E. Counsell, Kate S. M. Taylor, Robert Caslake, Angus D. Macleod, David J. M. McGhee, Diane Swallow; Research nurse/assistant: Joanne Gordon, Clare Harris, Ann Hayman, Nicola Johannesson, Hazel Forbes; Data management: Valerie Angus, Alasdair Finlayson, David Dawson, Katie Wilde, David Ritchie, Artur Wozniak; Statisticians: Neil Scott, Shona Fielding; Radiology: Prof. Alison Murray; Pathology: Ishbel Gall, Dr. James MacKenzie, Prof. Colin Smith; Secretarial: Aileen Sylvester, Susan Mitchell, Pam Rebecca, Ann Christie, and Diane McCosh. Funding agencies: This work was supported by the Research Council of Norway (287842). The CamPaIGN study has received funding from the Wellcome Trust, the Medical Research Council, the Patrick Berthoud Trust, and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The ICICLE-PD study was funded by Parkinson’s UK (J-0802, G-1301, G-1507) and supported by the Lockhart Parkinson’s Disease Research Fund, National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit and Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The NYPUM study was supported by grants from the Swedish Medical Research Council, Erling-Persson Foundation, the Swedish Brain Foundation (Hjärnfonden), Umeå University, Västerbotten County Council, King Gustaf V and Queen Victoria Freemason Foundation, Swedish Parkinson Foundation, Swedish Parkinson Research Foundation, Kempe Foundation, Swedish PD Association, the European Research Council, and the Knut and Alice Wallenberg Foundation. The Norwegian ParkWest study has received funding from the Research Council of Norway (177966), the Western Norway Regional Health Authority (911218), the Norwegian Parkinson’s Research Foundation, and Rebergs Legacy. The PICNICS study was funded by the Cure Parkinson’s Trust, the Van Geest Foundation, the Medical Research Council, Parkinson’s UK, and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The PINE study was funded by Parkinson’s UK (grant numbers G0502, G0914, and G1302), the Scottish Chief Scientist Office (CAF/12/05, PCL/17/10), Academy of Medical Sciences, NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, and SPRING. The PICC collaboration has been supported by The Chief Scientist Office of the Scottish Government (PCL/17/10), the Academy of Medical Sciences, Parkinson’s UK (initial collaborator meeting) and the Norwegian Association for Public Health. C.R.S.’s work was supported by NIH grants NINDS/NIA R01NS115144, U01NS095736, U01NS100603, and the American Parkinson Disease Association Center for Advanced Parkinson Research. This research was funded in whole, or in part by the UKRI Medical Research Council [MR/R007446/1]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

A Preference for a Sexual Signal Keeps Females Safe

Predation is generally thought to constrain sexual selection by female choice and limit the evolution of conspicuous sexual signals. Under high predation risk, females usually become less choosy, because they reduce their exposure to their predators by reducing the extent of their mate searching. However, predation need not weaken sexual selection if, under high predation risk, females exhibit stronger preferences for males that use conspicuous signals that help females avoid their predators. We tested this prediction in the fiddler crab Uca terpsichores by increasing females' perceived predation risk from crab-eating birds and measuring the attractiveness of a courtship signal that females use to find mates. The sexual signal is an arching mound of sand that males build at the openings of their burrows to which they attract females for mating. We found that the greater the risk, the more attractive were males with those structures. The benefits of mate preferences for sexual signals are usually thought to be linked to males' reproductive contributions to females or their young. Our study provides the first evidence that a female preference for a sexual signal can yield direct survival benefits by keeping females safe as they search for mates

Treatment of refractory epilepsy with natalizumab in a patient with multiple sclerosis. Case report

Background. Multiple sclerosis (MS) is considered an autoimmune disease of the central nervous system and therapeutic inhibition of leukocyte migration with natalizumab, an anti-alpha4 integrin antibody, is highly effective in patients with MS. Recent studies performed in experimental animal models with relevance to human disease suggested a key role for blood-brain barrier damage and leukocyte trafficking mechanisms also in the pathogenesis of epilepsy. In addition, vascular alterations and increased leukocyte accumulation into the brain were recently documented in patients with refractory epilepsy independently on the disease etiology. Case report. Here we describe the clinical course of a 24-year-old patient with MS in whom abrupt tonic-clonic generalized seizures manifested at disease onset. Although MS had a more favorable course, treatment with glatiramer acetate and antiepileptic drugs for 7 years had no control on seizure generation and the patient developed severe refractory epilepsy. Interestingly, generalized seizures preceded new MS relapses suggesting that seizure activity may contribute to MS worsening creating a positive feedback loop between the two disease conditions. Notably, treatment with natalizumab for 12 months improved MS condition and led to a dramatic reduction of seizures. Conclusion. Our case report suggests that inhibition of leukocyte adhesion may represent a new potential therapeutic approach in epilepsy and complement the traditional therapy with anti-epileptic drugs