RESUMO
BACKGROUND: Quantification of the T2 signal by means of T2 mapping in acute pancreatitis (AP) has the potential to quantify the parenchymal edema. Quantitative T2 mapping may overcome the limitations of previously reported scoring systems for reliable assessment of AP. PURPOSE: To evaluate MR-derived pancreatic T2 mapping values in AP and correlate them with markers of disease severity. STUDY TYPE: Prospective single-center study. POPULATION: 76 adults with AP (20-91 years, females/males: 39/37). FIELD STRENGTH/SEQUENCE: Fat suppressed multiecho spin-echo prototype sequence to quantify T2 signal at 3T MRI. ASSESSMENT: The severity of AP was assessed clinically, biologically, and by contrast-enhanced CT (CECT) performed 48-72 hours after symptom onset. MRI was then performed ≤24 hours after CT. Two readers blinded to any clinical information independently evaluated the T2 values by placing three regions of interest inside the pancreatic head, body, and tail on the T2 mapping MR sequence. Results were compared with corresponding CECT images as the standard and clinical severity parameters, using the length of hospital stay as our primary endpoint. STATISTICAL TESTS: Continuous variables were compared using the Spearman's rank correlation coefficient, analysis of variance (ANOVA) or Student's t-test. RESULTS: T2 values significantly correlated with the length of hospital stay (rs (74) = 0.29), CT severity index (CTSI) (rs (73) = 0.61; CTSI 0-3: 72 ± 14 msec, CTSI 4-10: 88 ± 15), intensive care unit (ICU) admission (t(2.77) = -3.41) and presence of organ failure (t(6.72) = -3.42), whereas the CTSI and Ranson score were not significantly related with ICU admission (CTSI: P = 0.24; Ranson score: P = 0.24) and organ failure (CTSI: P = 0.11; Ranson score P = 0.11). CONCLUSION: T2 mapping correlates with AP severity parameters and is useful for assessing the severity of AP with higher sensitivity than the usual clinical and radiological scoring systems. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.
RESUMO
BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. RESULTS: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. CONCLUSIONS: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
Assuntos
Deficiência Intelectual , Transcriptoma , Peixe-Zebra , Animais , Feminino , Humanos , Masculino , Deficiência Intelectual/genética , Mutação com Perda de Função , Mutação de Sentido Incorreto , Fenótipo , Peixe-Zebra/genéticaRESUMO
Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. Methods: Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +/+, DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN/DN or the LoF/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that AFF3 LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.