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

NfL as a biomarker for neurodegeneration and survival in Parkinson disease

OBJECTIVE: To determine if Neurofilament Light chain protein in cerebrospinal fluid (cNfL); a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in Parkinson's disease (PD). METHODS: We investigated if disease severity, phenotype or survival in patients with new-onset PD correlates with cNfL concentrations around the time of diagnosis in the population-based NYPUM study cohort (n = 99). A second, larger new-onset PD cohort (n = 194) was used for independent validation. Association of brain pathology with the cNfL concentration was examined using striatal dopamine transporter imaging and repeated diffusion tensor imaging, at baseline, 1 and 3 years. RESULTS: Higher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor, in both cohorts, and with shorter survival and impaired olfaction. cNfL concentrations above the median of 903 ng/L conferred an overall 5.8 times increased hazard of death, during follow-up. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts. CONCLUSIONS: cNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be of importance in future clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with PD, cNFL concentrations are associated with more severe disease and shorter survival

Invasive disease caused by Haemophilus influenzae in Sweden 1997–2009; evidence of increasing incidence and clinical burden of non‐type b strains

Introduction of a conjugated vaccine against encapsulated Haemophilus influenzae type b (Hib) has led to a dramatic reduction of invasive Hib disease. However, an increasing incidence of invasive disease by H. influenzae non‐type b has recently been reported. Non‐type b strains have been suggested to be opportunists in an invasive context, but information on clinical consequences and related medical conditions is scarce. In this retrospective study, all H. influenzae isolates ( n  =   410) from blood and cerebrospinal fluid in three metropolitan Swedish regions between 1997 and 2009 from a population of approximately 3 million individuals were identified. All available isolates were serotyped by PCR ( n  =   250). We observed a statistically significant increase in the incidence of invasive H. influenzae disease, ascribed to non‐typeable H. influenzae (NTHi) and encapsulated strains type f (Hif) in mainly individuals >60 years of age. The medical reports from a subset of 136 cases of invasive Haemophilus disease revealed that 48% of invasive NTHi cases and 59% of invasive Hif cases, respectively, met the criteria of severe sepsis or septic shock according to the ACCP/SCCM classification of sepsis grading. One‐fifth of invasive NTHi cases and more than one‐third of invasive Hif cases were admitted to intensive care units. Only 37% of patients with invasive non‐type b disease had evidence of immunocompromise, of which conditions related to impaired humoral immunity was the most common. The clinical burden of invasive non‐type b H. influenzae disease, measured as days of hospitalization/100 000 individuals at risk and year, increased significantly throughout the study period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87052/1/j.1469-0691.2010.03417.x.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/87052/2/CLM_3417_sm_FigS1.pd

Cytotoxicity, in Vivo Skin Irritation and Acute Systemic Toxicity of the Mesoporous Magnesium Carbonate Upsalite ®

Abstract Upsalite ® is a mesoporous magnesium carbonate synthesized without using surfactants and therefore highly attractive from environmental and production economy points of view. The material has recently been suggested as drug delivery vehicle and as topical bacteriostatic agent. In order to continue exploring these and other bio-related applications of the material, primary biocompatibility studies are needed. Herein we present the first in vivo acute systemic toxicity and skin irritation analyses as well as in vitro cytotoxicity evaluations of Upsalite ® . The material was found to be non-toxic for human dermal fibroblasts cells up to a concentration of 1000 µg/ml and 48 h exposure in contrast to the mesoporous silica material SBA-15, used as reference, which significantly affected cell viability at particle concentration of 500 and 1000 µg/ml after the same exposure time. Topical application of Upsalite ® resulted in negligible cutaneous reactions in a rabbit skin irritation model and no evidence of significant systemic toxicity was found when saline extracts of Upsalite ® were injected in mice. Injection of sesame oil extract, however, resulted in transient weight loss, most likely due to injection of particles, and not toxic leachables. The presented results form the basis for future development of Upsalite ® and similar mesoporous materials in biomedical applications and further toxicity as well as biocompatibility studies should be directed towards specific areas of use

PHYSIOLOGY AND MANAGEMENT Bovine Lactoferrin Receptors in Staphylococcus aureus Isolated from Bovine Mastitis

ABSTRACT A total of 103 Staphylococcus a w e w strains isolated from bovine mastitis were tested for bovine lactoferrin binding in a 1251-labeled protein binding assay. More than 85% of the strains demonstrated high to moderate and a few showed little or no binding. Bovine lactoferrin binding to S. aureus cells was high when grown on blood, nutrient, or proteose-peptone agar, but the binding capacity was low with cells grown on salt rich media, in skim milk, or in broth. The kinetics of 1251-labeled bovine lactoferrin binding required approximately 90 min for complete saturation with optimal interaction in the pH range 4.0 to 7.0. The lactoferrin-staphylococci interaction was specific with a high affinity (association constant, K, 14 x 106 L/mol). Scatchard plot analysis estimated the number of binding sites per cell at 7200 on strain SA-340. Unlabeled bovine lactoferrin effectively displaced the binding of the labeled ligand to strain SA-340 in a dosedependent manner. Abbreviation key: bLf = bovine lactoferrin, hLf = human lactoferrin, HRPO = horseradish peroxidase, Lf = lactoferrin, PBS = phosphatebuffered saline, PMN = polymorphonuclear leukocytes

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction Are Altered in Parkinson's Disease and Related Disorders

Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. Methods: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1 = 51, n2 = 101), corticobasal degeneration (CBD) (n1 = 11, n2 = 3), progressive supranuclear palsy (PSP) (n1 = 22, n2 = 21), multiple system atrophy (MSA) (n1 = 31, n2 = 26), and healthy control (HC) (n1 = 48, n2 = 30) participants, as well as Alzheimer's disease (AD) (n2 = 23) patients in the second cohort. Results: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25–0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate = −0.025 to −0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate = 0.32, P = 0.021). Conclusions: These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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

Predicting the Position of Attributive Adjectives in the French NP

Cet article est une version révisée de l'article paru dans Student session of the European Summer School for Logic, Language and Information, Copenhague : Danemark (2010)International audienceThis article proposes a quantitative study of the placement alternation for the adjective within the noun phrase in French. Taking the hypothesis that position constraints are mostly preferential as a starting point, we develop a methodology based on statistical inference in order to provide a formal account of the relative importance of different groups of constraints. Results show the relative importance of lexical constraints and that frequency-based and length constraints are the best predictors. This suggests that the placement of adjectives not only depends on our knowledge of lexical items but also on the knowledge of the way in which we use them in discourse, i.e. on usage

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