Immunity to MHC class I antigen after direct DNA transfer into skeletal muscle.

Plasmid cDNA encoding the alpha-chain of either membrane-bound (pcRT.45) or secreted (pcRQ.B3) RT1Aa MHC class I Ag were transferred to Lewis (RT1(1)) rat skeletal muscle by direct injection. Rats were challenged 7 days later with an ACI (RT1a) heterotropic heart transplant, and cardiac allograft survival, RT1Aa-specific antibody levels, and frequency of ACI-specific CTL were monitored. Graft rejection was accelerated by > or = 2 days in an Ag-specific and dose-dependent manner in pcRT.45-injected rats. The pcRQ.B3-injected rats also rejected grafts more rapidly; however, graft rejection was accelerated by only 1 day, and graft infiltrates were less pronounced than in pcRT.45-injected rats. Injection of pcRT.45 resulted in an increase in ACI-specific CTL precursor frequency 3 days post-transplant, whereas there was no significant change in rats pretreated with pcRQ.B3 injection. Compared with rats injected with a control plasmid encoding firefly luciferase, transfer of pcRT.45 resulted in an increase in RT1Aa-specific IgG and IgM antibody 3 days after heart transplantation. Transfer of pcRQ.B3 resulted in a similar mean increase in RT1Aa-specific IgG and IgM antibody after transplantation, but the variability from rat to rat was greater, with some animals exhibiting strong priming, and others showing little or no priming by gene injection. Our results suggest that skeletal muscle can express either membrane-bound or secreted MHC class I Ag after gene transfer, but that the membrane-bound form is more immunogenic than the secreted form in the high responder Lewis rat. Direct DNA transfer to skeletal muscle provides a rapid and specific approach to studying immunity to allogeneic MHC Ag

ISCCP CX observations during the FIRE/SRB Wisconsin Experiment from October 14 through November 2, 1986

Maps and tables are presented which show 45 satellite derived physical, radiation, or cloud parameters from ISCCP CX tapes during the FIRE/SRB Wisconsin experiment region from October 14 through November 2, 1986. Pixel locations selected for presentation are for an area which coincided with a 100 x 100 km array of evenly spaced ground truth sites. Area-averaged parameters derived from the ISSCP data should be consistent with area averages from the groundtruth stations

Use of donor serum to prevent passive transfer of hyperacute rejection

Organ transplantation in presensitized recipients continues to be contraindicated for heart and kidney recipients due to the risk of hyperacute rejection, which has no known treatment at this time. We tested whether donor serum, which contains soluble MHC class I antigen, is able to neutralize the effect of anti-donor antibody in the recipient and prevent hyperacute or accelerated rejection. A rat model of passive immunization was used to test the role of anti-donor antibody in hyperacute rejection. Seven of 10 recipients of hyperimmune serum (HyS), derived from Lewis rats (RT1l) following 3 ACI (RT1a) skin grafts, developed hyperacute or accelerated rejection. Intravenous injection of ACI serum prior to the HyS administration prevented hyperacute rejection in all recipients tested. When third-party (Wistar-Furth, RT1u) serum was given to Lewis rats injected with HyS, hyperacute rejection was not abrogated. When examining the mechanism of this effect, a simple antibody blocking phenomenon was found to be unlikely since flow cytometry analysis showed that ACI serum needed to be present at > or = 256-fold excess compared to HyS to block anti-ACI antibody binding to RT1.Aa+cells by 50%. We tested whether the RT1.Aa class I antigen in ACI serum had other biologic properties that resulted in the prolonged graft survival. However, removal of RT1.Aa antigen from ACI serum prior to use in the passive transfer model did not abrogate the graft prolongation observed previously. These data suggest that components of donor serum other than MHC class I antigen may be useful for preventing the antibody-mediated component of hyperacute rejection

Tribology: The Story of Lubrication and Wear

Topics addressed include: lubrication and design of high speed rolling element bearings, high speed gears, and traction drives

Assessment of linear-scale indices for perimetry in terms of progression in early glaucoma

AbstractCurrently, global indices that summarize the visual field combine sensitivities on a logarithmic (decibel) scale. Recent structure–function models for glaucoma suggest that contrast sensitivity should be converted to a linear scale before averaging across visual field locations, to better relate sensitivity with the number of surviving retinal ganglion cells (RGCs). New indices designed to represent the number of RGCs already lost are described. At least one was found to be a significantly better predictor of subsequent rate of change than traditional Mean Deviation (p=0.014) in participants with glaucomatous optic neuropathy. Issues concerning the creation of optimal global indices are discussed

Radiographic surveillance of minimally and moderately complex renal cysts

To assess the effectiveness of radiographic surveillance for managing minimally and moderately complex renal cysts. PATIENTS AND METHODS Forty-three patients with 50 minimally or moderately complex renal cysts underwent radiographic surveillance at our institution. Study inclusion criteria were surveillance for >2 years (36 patients, mean follow-up 3.0 years) or surveillance for >6 months with subsequent surgical excision (seven patients, mean follow-up 3.3 years). RESULTS The complexity of the renal cysts was in the form of high attenuation before contrast-enhanced imaging (‘hyperdense’) in 29 patients, thin septations in nine, borderline enhancement in six, thin calcifications in five, and a thick wall in one. The mean initial largest dimension was 2.9 cm and the mean final dimension was 3.0 cm, with the size increased in 29 cysts, decreased in 14 and with no change in seven. The cyst character worsened in seven patients, improved in four and did not change in 39. Eventually seven patients had surgery (laparoscopic partial nephrectomy in five and laparoscopic radical nephrectomy in two), which revealed renal cancer in five. Surgical intervention was prompted by growth alone in two patients, growth and worsening of cyst characteristics in two, new onset of flank pain in one, and appearance of an enhancing nodule in the wall or septa in two. CONCLUSION Radiographic surveillance is an effective method for managing patients with minimally or moderately complex renal cysts. Malignant lesions can be identified and removed while still of low grade and contained, and surgery can be avoided in most patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72374/1/j.1464-410X.2008.08171.x.pd

Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat

Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat. Tubulointerstitial fibrosis is one of the most important histologic features that predicts progression in kidney disease. Thrombospondin 1 is an extracellular matrix protein that can activate latent TGF-β, a cytokine implicated in the pathogenesis of tubulointerstitial fibrosis. We examined the expression of thrombospondin 1 in several animal models of glomerulonephritis (anti-Thy1 model, aminonucleoside nephrosis, passive Heymann nephritis) that are associated with tubulointerstitial disease. Thrombospondin 1 mRNA and protein were transiently increased in tubular cells, myofibroblasts and some macrophages in areas of tubulointerstitial injury. Thrombospondin 1 expression always preceded the development of tubulointerstitial fibrosis, and correlated quantitatively and spatially with the later development of interstitial fibrosis. Thrombospondin 1 expression predicted the severity of tubulointerstitial fibrosis better than the degree of macrophage or myofibroblast accumulation. Thrombospondin 1 expression was associated with increased expression and activation of TGF-β1 and decreased expression of LAP-TGF-β in areas of tubulointerstitial injury. We conclude that thrombospondin 1 is an early marker predicting the development of tubulointerstitial kidney disease. De novo expression of thrombospondin 1 is associated and colocalized with increased expression of TGF-β1 and decreased expression of LAP-TGF-β during the development of tubulointerstitial disease in vivo. These data are consistent with the possibility that thrombospondin 1 may be an endogenous activator of TGF-β

Dissolved organic carbon uptake in streams: A review and assessment of reach‐scale measurements

Quantifying the role that freshwater ecosystems play in the global carbon cycle requires accurate measurement and scaling of dissolved organic carbon (DOC) removal in river networks. We reviewed reach‐scale measurements of DOC uptake from experimental additions of simple organic compounds or leachates to inform development of aquatic DOC models that operate at the river network, regional, or continental scale. Median DOC uptake velocity (vf) across all measurements was 2.28 mm min−1. Measurements using simple compound additions resulted in faster vf (2.94 mm min−1) than additions of leachates (1.11 mm min−1). We also reviewed published data of DOC bioavailability for ambient stream water and leaf leachate DOC from laboratory experiments. We used these data to calculate and apply a correction factor to leaf leachate uptake velocity to estimate ambient stream water DOC uptake rates at the reach scale. Using this approach, we estimated a median ambient stream DOC vf of 0.26 mm min−1. Applying these DOC vf values (0.26, 1.11, 2.28, and 2.94 mm min−1) in a river network inverse model in seven watersheds revealed that our estimated ambient DOC vf value is plausible at the network scale and 27 to 45% of DOC input was removed. Applying the median measured simple compound or leachate vf in whole river networks would require unjustifiably high terrestrial DOC inputs to match observed DOC concentrations at the basin mouth. To improve the understanding and importance of DOC uptake in fluvial systems, we recommend using a multiscale approach coupling laboratory assays, with reach‐scale measurements, and modeling

Heavy cannabis use is associated with low bone mineral density and an increased risk of fractures

Purpose: To investigate possible associations between recreational cannabis use and bone health in humans.  Methods: Cross-sectional study of individuals recruited from primary care in the UK between 2011 and 2014. Cases were regular smokers of cannabis divided into moderate (n=56) and heavy user (n=144) subgroups depending on whether they reported fewer or more than 5000 cannabis smoking episodes during their lifetime. Controls comprised 114 cigarette smokers.  Results: Heavy cannabis users had lower total hip bone mineral density (mean ± SD Z-score: -0.20±0.9 vs. +0.2±0.9, p<0.0005), lower spine bone mineral density (-0.5±1.2 vs. 0.0±1.2, p<0.0005) and lower BMI (26.5±6.0 vs 29.0±7.0, p=0.01) than controls. Fracture rate was also increased in heavy users (rate ratio=2.17, 95% confidence interval 1.59 to 2.95; p<0.001). When compared with controls, CTX serum concentrations were raised in heavy cannabis users (0.3±0.1 vs. 0.2±0.1 pg/ml, p=0.045) as were P1NP concentrations (47.1±19.2 vs. 41.2±17.8 pg/ml, p=0.01). Serum 25(OH)D concentrations were reduced in heavy users compared with controls (25.3±16.8 vs. 36.9±26.7 nmol/l, p=0.002). Multiple regression analysis revealed that heavy cannabis use was an independent predictor of spine bone mineral density accounting for 5.4% of the variance (p=0.035) and total hip bone mineral density accounting for 5.8% of the variance (p=0.001) but mediation analysis suggested that the effect on spine bone mineral density was indirect and mediated through low BMI.  Conclusion: Heavy cannabis use is associated with low bone mineral density, low BMI, high bone turnover and an increased risk of fracture. Heavy cannabis use negatively impacts on bone health both directly and indirectly through an effect on BMI

The prevalence of long COVID in people with diabetes mellitus–evidence from a UK cohort

Background: It was apparent from the early phase of the SARS-CoV-2 virus (COVID-19) pandemic that a multi-system syndrome can develop in the weeks following a COVID-19 infection, now referred to as Long COVID. Given that people living with diabetes are at increased risk of hospital admission/poor outcomes following COVID-19 infection we hypothesised that they may also be more susceptible to developing Long COVID. We describe here the prevalence of Long COVID in people living with diabetes when compared to matched controls in a Northwest UK population. Methods: This was a retrospective cohort study of people who had a recorded diagnosis of type 1 diabetes (T1D) or type 2 diabetes (T2D) who were alive on 1st January 2020 and who had a proven COVID-19 infection. We used electronic health record data from the Greater Manchester Care Record collected from 1st January 2020 to 16th September 2023, we determined the prevalence of Long COVID in people with T1D and T2D vs matched individuals without diabetes (non-DM). Findings: There were 3087 T1D individuals with 14,077 non-diabetes controls and 3087 T2D individuals with 14,077 non-diabetes controls and 29,700 T2D individuals vs 119,951 controls. For T1D, there was a lower proportion of Long COVID diagnosis and/or referral to a Long COVID service at 0.33% vs 0.48% for matched controls. The prevalence of Long COVID In T2D individuals was 0.53% vs 1:3 matched controls 0.54%. For T2D, there were differences by sex in the prevalence of Long COVID in comparison with 1:3 matched controls. For Long COVID between males with T2D and their matched controls, the prevalence was lower in matched controls at 0.46%.vs 0.54% (0.008). When considering the prevalence of LC between females with T2D and their matched controls, the prevalence was higher in matched controls at 0.61% vs 0.53% (0.007). The prevalence of Long COVID in males with T2D vs females was not different. T2D patients at older vs younger age were at reduced risk of developing Long COVID (OR 0.994 [95% CI) [0.989, 0.999]). For females there was a minor increase of risk (OR 1.179, 95% CI [1.002, 1.387]). Presence of a higher body mass index (BMI) was also associated an increased risk of developing Long COVID (OR 1.013, 95% CI [1.001, 1.026]). The estimated general population prevalence of Long COVID based on general practice coding (not self-reported) of this diagnosis was 0.5% of people with a prior acute COVID-19 diagnosis. Interpretation: Recorded Long COVID was more prevalent in men with T2D than in matched non-T2D controls with the opposite seen for T2D women, with recorded Long COVID rates being similar for T2D men and women. Younger age, female sex and higher BMI were all associated with a greater likelihood of developing Long COVID when taken as individual variables. There remains an imperative for continuing awareness of Long COVID as a differential diagnosis for multi-system symptomatic presentation in the context of a previous acute COVID-19 infection. Funding: The time of co-author RW was supported by the NIHR Applied Research Collaboration Greater Manchester ( NIHR200174) and the NIHR Manchester Biomedical Research Centre ( NIHR203308)