Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain–related gene A, ...MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio HR, 1.83; 95% confidence interval CI, 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.
•Matching for MICA significantly reduces the incidence of acute and chronic GVHD in otherwise HLA 10/10-matched unrelated-donor HCT.•Our results formally define MICA as a novel major histocompatibility complex-encoded human transplantation antigen.
Return to play (RTP) decisions in football are currently based on expert opinion. No consensus guideline has been published to demonstrate an evidence-based decision-making process in football ...(soccer). Our aim was to provide a framework for evidence-based decision-making in RTP following lower limb muscle injuries sustained in football. A 1-day consensus meeting was held in Milan, on 31 August 2018, involving 66 national and international experts from various academic backgrounds. A narrative review of the current evidence for RTP decision-making in football was provided to delegates. Assembled experts came to a consensus on the best practice for managing RTP following lower limb muscle injuries via the Delphi process. Consensus was reached on (1) the definitions of ‘return to training’ and ‘return to play’ in football. We agreed on ‘return to training’ and RTP in football, the appropriate use of clinical and imaging assessments, and laboratory and field tests for return to training following lower limb muscle injury, and identified objective criteria for RTP based on global positioning system technology. Level of evidence IV, grade of recommendation D.
Background: Graft-versus-host disease (GVHD) is a major cause of mortality after unrelated hematopoietic stem cell transplantations (HSCT). Despite the development of modern immunosuppressive ...strategies, a nearly perfectly controlled compatibility of the classical HLA genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) and availability of numerous so-called minor histocompatibility antigens (e.g. HY or HA-1), its incidence remains largely unexplained to date. MIC genes (MHC class I chain-related) - a distinct lineage of MHC class I genes – are promising candidates to explain, at least partially, the incidence of GVHD in HLA-matched transplantations. MICA and MICB are highly polymorphic (100 alleles for MICA and 40 for MICB) and encode functional cell-surface glycoproteins up-regulated by cell stress. They interact with NKG2D, an activating receptor expressed on the surface of cytotoxic αβ CD8+ and γδ T lymphocytes and natural killer cells. MIC genes are already known to have a HLA-independent effect on solid graft outcomes and may play a similar role in HSCT by triggering GVHD.
Objective: The objective of the present study was to determine the impact of donor/patient matching at the MICA and MICB loci on the incidence of GVHD in patients undergoing unrelated HSCT.
Methods: We retrospectively analyzed a multicenter cohort of 1072 unrelated transplantations performed between 1996 and 2013. All donor-recipient pairs were fully typed at high resolution for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 and were matched for ten of ten HLA alleles (HLA 10/10 matched). High resolution genotyping of MICA and MICB was performed by sequenced-based typing in order to define matching grades between donors and patients. The endpoints of the study were acute and chronic GVHD. Apart from HLA-DPB1 matching, statistical models were adjusted for major clinical variables which have been shown to be associated with outcome (patient’s age, patient’s and donor’s sex, patient’s and donor’s serological status for cytomegalovirus, year of transplantation, time to transplantation, transplantation center, source of stem cells, conditioning regimen, GVHD prophylaxis, treatment with anti-thymocyte globulin, disease category and severity at transplantation).
Results: Of the 1072 transplantations, 134 (12.5 %) and 380 (35.4 %) were mismatched at the MICA and MICB locus, respectively. Both MICA and MICB mismatches were significantly associated with an increased incidence of severe acute GVHD (grades III-IV) in univariate and multivariate models (multivariate model: HR = 2.32, 95 % CI = 1.84-2.92; p=0.0003 for MICA and HR = 1.49, 95 % CI = 1.24-1.79; p=0.03 for MICB). At day 100 post-HSCT severe acute GVHD incidences in mismatched vs. matched transplantations were 19.62 % vs. 15.08 % and 20.00 % vs. 14.84 % for MICA and MICB, respectively (Figure 1). Chronic GVHD was associated with MICA and MICB mismatches in univariate analysis (HR = 1.55, 95 % CI = 1.27-1.89; p=0.029 for MICA and HR=1.38, 95 % CI = 1.19-1.62; p=0.03 for MICB), but showed only a trend for association in multivariate models.
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Conclusion: To date this is the largest reported MICA and MICB sequence analysis whether in HSCT or solid organ transplantation. Inclusion of MICA and MICB typing in the donor selection process may be a practical clinical strategy for lowering the risks of severe acute GVHD after unrelated HSCT.
No relevant conflicts of interest to declare.
Történet az aranyhalról Edmond Séchan, rendező/ forgatókönyv; Roger Mauge, forgatkönyvíró; Pierre Goupill, operatőr ...
1959
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Provider: - Institution: - Data provided by Europeana Collections- Text of censorship. The bulk of the film entails a fish swimming happily in his bowl while his new owner, a little boy, is away at ...school. A cat enters the room where the fish and his bowl are, and begins to stalk his "prey." The boy begins his walk home from school, and the viewer wonders whether he arrives in time to save his fish friend. The fish becomes agitated by the cat's presence, and finally jumps out of the bowl! The cat quickly walks over to the fish, gently picks him up with his paws, and returns him to his bowl. The boy returns happily to his fish.- A film során Párizsban egy keleti származású gyári munkásasszony fia elmegy tejért. Útközben egy szép aranyhalacskában gyönyörködik. Szeretné megvenni, de a pénzt tejre kapta. Váratlan fordulatok során egy férfi pénzt ad neki, amivel nyer annyi pénzt, hogy meg tudja venni az aranyhalat. Boldogan viszi haza, ahol már van egy kanári madara. Másnap iskola után vesz neki egy kis növényt az akváriumot helyettesítő üvegbe, és nem is tudja, otthon milyen drámai események zajlanak egy macska, az aranyhal és a kanári között. A macskának a kanárira fáj a foga, de megszaglássza az aranyhalacskát is...
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