Toxoplasma gondii is a zoonotic intracellular parasite, able to infect any warm-blooded animal via ingestion of infective stages, either contained in tissue cysts or oocysts released into the environment. While immune responses during infection are well-studied, there is still limited knowledge about the very early infection events in the gut tissue after infection via the oral route. Here we briefly discuss differences in host-specific responses following infection with oocyst-derived sporozoites vs. tissue cyst-derived bradyzoites. A focus is given to innate intestinal defense mechanisms and early immune cell events that precede T. gondii's dissemination in the host. We propose stem cell-derived intestinal organoids as a model to study early events of natural host-pathogen interaction. These offer several advantages such as live cell imaging and transcriptomic profiling of the earliest invasion processes. We additionally highlight the necessity of an appropriate large animal model reflecting human infection more closely than conventional infection models, to study the roles of dendritic cells and macrophages during early infection.
Objective: Surgical knee joint distraction (KJD) leads to clinical improvement in knee osteoarthritis (OA) and also apparent cartilage regeneration by magnetic resonance imaging. We investigated if alteration of the joint's mechanical environment during the 6 week period of KJD was associated with a molecular response in synovial fluid, and if any change was associated with clinical response. Method: 20 individuals undergoing KJD for symptomatic radiographic knee OA had SF sampled at baseline, midpoint and endpoint of distraction (6 weeks). SF supernatants were measured by immunoassay for 10 predefined mechanosensitive molecules identified in our previous pre-clinical studies. The composite Knee injury and OA Outcome Score-4 (KOOS 4) was collected at baseline, 3, 6 and 12 months. Results: 13/20 (65%) were male with mean age 54 ± 5yrs. All had KellgreneLawrence grade !2 knee OA. 6/10 analytes showed statistically significant change in SF over the 6 weeks distraction (activin A; TGFb-1; MCP-1; IL-6; FGF-2; LTBP2), P < 0.05. Of these, all but activin A increased. Those achieving the minimum clinically important difference of 10 points for KOOS 4 over 6 months showed greater increases in FGF-2 and TGFb-1 than non-responders. An increase in IL-8 during the 6 weeks of KJD was associated with significantly greater improvement in KOOS 4 over 12 months. Conclusion: Detectable, significant molecular changes are observed in SF following KJD, that are remarkably consistent between individuals. Preliminary findings appear to suggest that increases in some molecules are associated with clinically meaningful responses. Joint distraction may provide a potential opportunity in the future to define regenerative biomarker(s) and identify pathways that drive intrinsic cartilage repair.
Background Joint injury is a major risk factor for osteoarthritis and provides an opportunity to prospectively examine early processes associated with osteoarthritis. We investigated whether predefined baseline demographic and clinical factors, and protein analytes in knee synovial fluid and in plasma or serum, were associated with clinically relevant outcomes at 2 years after knee injury.Methods This longitudinal cohort study recruited individuals aged 16-50 years between Nov 1, 2010, and Nov 28, 2014, across six hospitals and clinics in London, UK. Participants were recruited within 8 weeks of having a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically treated surgically. We measured several predefined clinical variables at baseline (eg, time from injury to sampling, extent and type of joint injury, synovial fluid blood staining, presence of effusion, self-reported sex, age, and BMI), and measured 12 synovial fluid and four plasma or serum biomarkers by immunoassay at baseline and 3 months. The primary outcome was Knee Injury and Osteoarthritis Outcome Score (KOOS 4 ) at 2 years, adjusted for baseline score, assessed in all patients. Linear and logistic regression models adjusting for predefined covariates were used to assess associations between baseline variables and 2-year KOOS 4 . This study is registered with ClinicalTrials.gov, number NCT02667756. FindingsWe enrolled 150 patients at a median of 17 days (range 1-59, IQR 9-26) after knee injury. 123 (82%) were male, with a median age of 25 years (range 16-50, IQR 21-30). 98 (65%) of 150 participants completed a KOOS 4 at 2 (or 3) years after enrolment (50 participants were lost to follow-up and two were withdrawn due to adverse events unrelated to study participation); 77 (51%) participants had all necessary variables available and were included in the core variable adjusted analysis. In the 2-year dataset mean KOOS 4 improved from 38 (SD 18) at baseline to 79 (18) at 2 years. Baseline KOOS 4, medium-to-large knee effusion, and moderate-to-severe synovial blood staining and their interaction significantly predicted 2-year KOOS 4 (n=77; coefficient -20•5, 95% CI -34•8 to -6•18; p=0•0060). The only predefined biomarkers that showed independent associations with 2-year KOOS 4 were synovial fluid MCP-1 (n=77; -0•015, 0•027 to -0•004 per change in 1 pg/mL units; p=0•011) and IL-6 (n=77; -0•0005, -0•0009 to -0•0001 per change in 1 pg/mL units; p=0•017). These biomarkers, combined with the interaction of effusion and blood staining, accounted for 39% of outcome variability. Two adverse events occurred that were linked to study participation, both at the time of blood sampling (one presyncopal episode, one tenderness and pain at the site of venepuncture).Interpretation The combination of effusion and haemarthrosis was significantly associated with symptomatic outcomes after acute knee injury. The synovial fluid molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently as...
This retrospective case-control study assessed the impact of bilateral salpingectomy due to uni- or bilateral hydrosalpinges on the outcome of in-vitro fertilization (IVF) in a large consecutive series of patients. The effect of bilateral salpingectomy due to hydrosalpinges on pregnancy outcome was compared in 139 patients (263 cycles) and 139 age-matched controls with tubal infertility without hydrosalpinges (296 cycles). The delivery rates per initiated cycle as well as the implantation rates were equal in the two groups (21.7 versus 21.6% and 19 versus 21%). The number of embryos, the cleavage stage, and the embryo morphology score were equal in the two groups. Among 92 patients treated with 182 IVF cycles who underwent salpingectomy between 1.5 and 5 years prior to their first IVF cycle, the delivery and the implantation rates were 22.5 and 20.5% respectively. Of the patients with salpingectomy after an average of 1.7 failed IVF cycles and who re-entered the IVF programme 3 and 6 months subsequent to surgery, 47 were treated with 83 IVF cycles. The live birth and the implantation rates after surgery in this group were 20.5 and 20% respectively. It is concluded that bilateral salpingectomy due to hydrosalpinges restores a normal delivery as well as implantation rate after IVF treatment compared to controls. A favourable outcome is also found in patients operated on after repeated IVF failures. Furthermore, a normal live birth rate as well as a high implantation rate is maintained for at least three IVF cycles subsequent to surgical treatment.
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