Numerical simulations of delamination in fibre reinforced plastic shell structures using XFEM

[no abstract

Lymphangiogenesis in renal diseases

Lymphatic vessels (LVs) are thin walled structures that transport lymph from tissues to lymph nodes. By this function they are complementary to the cardiovascular system in the maintenance of body fluid homeostasis. They play a pivotal role in many (patho)-physiological processes, such as inflammation, immune surveillance and tolerance, fat abortion and metabolism, and general tissue homeostasis, and are involved in disease conditions as diverse as hypertension, atherosclerosis, transplant rejection and survival, and tumor metastasis. Although our understanding has been improved substantially, the biology of LVs is still in its infancy. During recent years many details have emerged as to how LVs function in diseased states, mostly in cancer related conditions. However, the functional significance of the lymphatic network in individual organ health and disease is still poorly understood. Data obtained in kidney transplantation, albeit few, support the important role of LV in intra-organ pathophysiology. Lymphangiogenesis, the outgrowth of preexisting and genesis of new LVs, is an important component of the tissue response to microenvironmental changes, and can have huge impact on disease progression and tissue homeostasis. In the present thesis, we have provided more insight into the mechanistical role of lymphatic vessels (LVs) and lymphangiogenesis in the pathophysiology of renal diseases. To this end, we evaluated whether lymphangiogenesis occurs in renal disease conditions, and if so, whether lymphangiogenesis associates with the degree of renal damage. Even more important, we studied whether targeting lymphangiogenesis can pose a beneficial therapeutic effect in experimental models of kidney injury

Istraživanje patoloških promjena kod celulitisa uzrokovanog bakterijom Erysipelothrix rhusiopathiae u pokusno zaraženih tovnih pilića.

Avian cellulitis is a serious problem for the commercial broiler industry. Although various agents were isolated from cellulitis lesions, the ability of Erysipelothrix rhusiopathiae in reproduction of cellulitis is not known. Therefore, the objective of this study was to evaluate the ability of these bacteria for induction of avian cellulitis. The study involved two experimental groups, each consisting of twenty randomly selected 15-day-old, mixed sex, healthy, commercially grown broiler chickens of the same strain. A single scratch was induced with a 1.5-inch 18-gauge needle, creating a lesion 2 cm in length on the right dorsolateral surface of the body parallel to the vertebrae. In Group 1, 1ml of 10² bacterial suspension - isolated from a turkey cock with erysipelas - was inoculated into the scratches. Birds in Group 2 received 1ml of the sterile phosphate-buffered saline as negative controls. At 48-hr post inoculation the birds were killed and pathologic and bacteriologic examinations were carried out. Birds in Group1 showed weakness, depression and mild diarrhoea. In this group, 65% of birds showed swelling of the skin with necrosis, infiltration of heterophils and fibrinous exudates, which was characteristic of cellulitis. The remaining 35% of birds were dead within 24-hrs post inoculation, with signs of mild cellulitis. Erysipelothrix rhusiopathiae was recovered from skin and some other internal organs from birds in Group 1. Birds in Group 2 were normal. Results of the present study revealed that E. rhusiopathiae can be considered as a causative agent of avian cellulitis, with public health hazards.Celulitis peradi ozbiljan je problem u proizvodnji tovnih pilića. Iako su različiti agensi izdvojeni iz celulitičnih lezija, sposobnost Erysipelothrix rhusiopathiae u izazivanju celulitisa nije poznata. Stoga je cilj ovog istraživanja bio istražiti ulogu ove bakterije u nastanku celulitisa peradi. Korištene su dvije pokusne skupine, od kojih je svaka bila sastavljena od nasumce odabranih dvadeset komercijalno uzgajanih, zdravih, petnaestodnevnih tovnih pilića, mješovita spolnog sastava i istog soja. Na desnoj dorzolateralnoj strani tijela peralelno s kralježnicom, iglom je načinjena ogrebotina duga 2 cm. Pilićima jedne skupine u tu je ogrebotinu inokuliran 1 ml suspenzije s 102 bakterijskih stanica uzročnika izdvojenog iz purana s vrbancem. Pilići druge skupine primili su 1 ml sterilne puferirane otopine fosfatne soli kao negativnu kontrolu. Pilići su bili žrtvovani 48 sati nakon inokulacije, a potom su načinjena patološka i bakteriološka istraživanja. U 65% pilića iz prve skupine uočeno je otečenje kože s nekrozama, infiltracija heterofila i fibrinozni eksudat, što je osebujno za celulitis. Preostalih 35% pilića je uginulo unutar 24 sata nakon inokulacije sa znakovima blagog celulitisa. Erysipelothrix rhusiopathiae bio je ustanovljen u koži i nekim unutarnjim organima pilića iz prve skupine. Pilići iz druge skupine bili su zdravi. Rezultati ovog istraživanja pokazuju da se E. rhusiopathiae može smatrati uzročnikom celulitisa peradi i predstavlja opasnost za javno zdravstvo

Proteinuria converts hepatic heparan sulfate to an effective proprotein convertase subtilisin kexin type 9 enzyme binding partner:a historical appraisal of its origins and conceptual evolution

International audienc

Targeting tubulointerstitial remodeling in proteinuric nephropathy in rats

Proteinuria is an important cause of tubulointerstitial damage. Anti-proteinuric interventions are not always successful, and residual proteinuria often leads to renal failure. This indicates the need for additional treatment modalities by targeting the harmful downstream consequences of proteinuria. We previously showed that proteinuria triggers renal lymphangiogenesis before the onset of interstitial inflammation and fibrosis. However, the interrelationship of these interstitial events in proteinuria is not yet clear. To this end, we specifically blocked lymphangiogenesis (anti-VEGFR3 antibody), monocyte/macrophage influx (clodronate liposomes) or lymphocyte and myofibroblast influx (S1P agonist FTY720) separately in a rat model to investigate the role and the possible interaction of each of these phenomena in tubulointerstitial remodeling in proteinuric nephropathy. Proteinuria was induced in 3-month old male Wistar rats by adriamycin injection. After 6 weeks, when proteinuria has developed, rats were treated for another 6 weeks by anti-VEGFR3 antibody, clodronate liposomes or FTY720 up to week 12. In proteinuric rats, lymphangiogenesis, influx of macrophages, T cells and myofibroblasts, and collagen III deposition and interstitial fibrosis significantly increased at week 12 vs week 6. Anti-VEGFR3 antibody prevented lymphangiogenesis in proteinuric rats, however, without significant effects on inflammatory and fibrotic markers or proteinuria. Clodronate liposomes inhibited macrophage influx and partly reduced myofibroblast expression; however, neither significantly prevented the development of lymphangiogenesis, nor fibrotic markers and proteinuria. FTY720 prevented myofibroblast accumulation, T-cell influx and interstitial fibrosis, and partially reduced macrophage number and proteinuria; however, it did not significantly influence lymphangiogenesis and collagen III deposition. This study showed that proteinuria-induced interstitial fibrosis cannot be halted by blocking lymphangiogenesis or the influx of macrophages. On the other hand, FTY720 treatment did prevent T-cell influx, myofibroblast accumulation and interstitial fibrosis, but not renal lymphangiogenesis and proteinuria. We conclude that tubulointerstitial fibrosis and inflammation are separate from lymphangiogenesis, at least under proteinuric conditions

Urinary collagen degradation products as early markers of progressive renal fibrosis

Background: Renal fibrogenesis is associated with increased ECM remodeling and release of collagen fragments in urine in progressive renal disease. We investigated the diagnostic value of urinary collagen degradation products in a proteinuria-driven fibrosis rat model with and without anti-fibrotic S1P-receptor modulator FTY720 treatment. Methods: Proteinuria was induced in male Wistar rats by Adriamycin (ADR) injection (n = 16). Healthy rats served as controls (n = 12). Six weeks post-injection, all underwent renal biopsy, and FTY720-treatment started in ADR-rats (n = 8) and controls (n = 6). Others remained untreated. Rats were sacrificed after 12 weeks. Collagen type I (C1M) and III (C3M) degradation fragments were measured in blood and urine using ELISA. Kidneys were stained for various inflammatory and fibrotic markers. Results: Six weeks post-injection proteinuria increased (versus controls, P <0.001) and although no accumulation of interstitial renal collagen type III (iColl3) was observed at this time, urinary C3M (uC3M) and C1M (uC1M) were significantly increased (both P <0.001). At 12 weeks, uC3M (P <0.001) and uC1M (P <0.01) further increased in ADR-rats versus controls, just as fibronectin, PDGF-beta receptor, hyaluronan (all P <0.01), iColl3, PAS, myofibroblasts, macrophages and T-cells (all P <0.05). FTY720-treatment reduced accumulation of immune cells, alpha-SMA+ myofibroblasts and PAS-score, but not iColl3 and uC3M. Correlation analyses indicated that uC3M and uC1M reflected and predicted tubulointerstitial fibrogenesis. Conclusions: These data displayed urinary collagen breakdown products as sensitive early markers of interstitial fibrosis, preceding histological fibrotic changes, which might replace the invasive renal biopsy procedure to assess fibrosis. Anti-fibrotic FTY720 intervention reduced some fibrotic markers without affecting collagen type III metabolism

Global estimates on the number of people blind or visually impaired by cataract: a meta-analysis from 2000 to 2020

Background: To estimate global and regional trends from 2000 to 2020 of the number of persons visually impaired by cataract and their proportion of the total number of vision-impaired individuals. Methods: A systematic review and meta-analysis of published population studies and gray literature from 2000 to 2020 was carried out to estimate global and regional trends. We developed prevalence estimates based on modeled distance visual impairment and blindness due to cataract, producing location-, year-, age-, and sex-specific estimates of moderate to severe vision impairment (MSVI presenting visual acuity &lt;6/18, ≥3/60) and blindness (presenting visual acuity &lt;3/60). Estimates are age-standardized using the GBD standard population. Results: In 2020, among overall (all ages) 43.3 million blind and 295 million with MSVI, 17.0 million (39.6%) people were blind and 83.5 million (28.3%) had MSVI due to cataract blind 60% female, MSVI 59% female. From 1990 to 2020, the count of persons blind (MSVI) due to cataract increased by 29.7%(93.1%) whereas the age-standardized global prevalence of cataract-related blindness improved by −27.5% and MSVI increased by 7.2%. The contribution of cataract to the age-standardized prevalence of blindness exceeded the global figure only in South Asia (62.9%) and Southeast Asia and Oceania (47.9%). Conclusions: The number of people blind and with MSVI due to cataract has risen over the past 30 years, despite a decrease in the age-standardized prevalence of cataract. This indicates that cataract treatment programs have been beneficial, but population growth and aging have outpaced their impact. Growing numbers of cataract blind indicate that more, better-directed, resources are needed to increase global capacity for cataract surgery.</p

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions. Funding: Bill &amp; Melinda Gates Foundation