Research Spotlight

Choquet, K., D. Forget, E. Meloche, M. J. Dicaire, G. Bernard, A. Vanderver, R. Schiffmann, M. R. Fabian, M. Teichmann, B. Coulombe, B. Brais and C. L. Kleinman (2019). “Leukodystrophy-associated POLR3A mutations down-regulate the RNA polymerase III transcript and important regulatory RNA BC200.” J Biol Chem Mar 21. [Epub ahead of print].

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RNA polymerase III (Pol III) is an essential enzyme responsible for the synthesis of several small non-coding RNAs, a number of which are involved in mRNA translation. Recessive mutations in POLR3A, encoding the largest subunit of Pol III, cause POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), characterized by deficient central nervous system myelination. Identification of the downstream effectors of pathogenic POLR3A mutations has been so far elusive. Here, we used CRISPR-Cas9 to introduce the POLR3A mutation c.2554A>G (p.M852V) into human cell lines and assessed its impact on Pol III biogenesis, nuclear import, DNA occupancy, transcription, and protein levels. Transcriptomic profiling uncovered a subset of transcripts vulnerable to Pol III hypofunction, including a global reduction in tRNA levels. The brain cytoplasmic BC200 RNA (BCYRN1), involved in translation regulation, was consistently affected in all our cellular models, including patient-derived fibroblasts. Genomic BC200 deletion in an oligodendroglial cell line led to major transcriptomic and proteomic changes, having a larger impact than those of POLR3A mutations. Upon differentiation, mRNA levels of the MBP gene, encoding myelin basic protein, were significantly decreased in POLR3A-mutant cells. Our findings provide the first evidence for impaired Pol III transcription in cellular models of POLR3-HLD and identify several candidate effectors, including BC200 RNA, having a potential role in oligodendrocyte biology and involvement in the disease.

Banerjee, T., D. Crews, D. E. Wesson, C. McCulloch, K. Johansen, S. Saydah, N. Rios Burrows, R. Saran, B. Gillespie, J. Bragg-Gresham and N. R. Powe (2019). “Elevated Serum Anion Gap in Adults with Moderate Chronic Kidney Disease Increases Risk for Progression to End Stage Renal Disease.” Am J Physiol Renal Physiol Mar 25. [Epub ahead of print].

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BACKGROUND: Acid retention associated with reduced GFR exacerbates nephropathy progression in partial nephrectomy models of CKD and might be reflected in CKD patients with reduced eGFR by increased anion gap (AG). METHODS: We explored the presence of AG and its association with CKD in 14,924 adults, aged >/=20 years and eGFR>/=15ml/min/1.73m(2), enrolled in the National Health and Nutrition Examination Survey III, 1988-1994 using multivariable regression analysis. The model was adjusted for socio-demographic characteristics, diabetes, and hypertension. We further examined the association between AG and incident end-stage renal disease using frailty models, adjusting for demographics, clinical factors, BMI, serum albumin, bicarbonate, eGFR, and urinary albumin-to-creatinine ratio, by following 558 adults with moderate CKD for 12 years via the United States Renal Data System. Laboratory measures determined AG using the traditional, albumin-corrected, and full AG definitions. RESULTS: Individuals with moderate CKD (eGFR 30-59 ml/min/1.73 m(2)) had a greater AG than those with eGFR>/=60 ml/min in multivariable regression analysis with adjustment for covariates. We found a graded relationship between the adjusted mean for all three definitions of AG and eGFR categories (p trend<0.0001). During follow-up, 9.2% of adults with moderate CKD developed ESRD. Those with AG in the highest tertile had a higher risk of ESRD, after adjusting for covariates in a frailty model (Relative risk [95% CI] for traditional AG:1.8[1.2-2.3]), compared to those in the middle tertile. CONCLUSIONS: The data suggest that high AG, even after adjusting for serum bicarbonate, is a contributing acid-base mechanism to CKD progression in moderate CKD.

Armstrong, T. W., M. L. C. Williamson, T. R. Elliott, W. T. Jackson, N. T. Kearns and T. Ryan (2019). “Psychological distress among persons with upper extremity limb loss.” Br J Health Psychol Apr 3. [Epub ahead of print].

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OBJECTIVE: We examined predictors of clinically significant levels of psychological distress among individuals with upper limb loss (ULL). DESIGN: A multisite, cross-sectional study completed at six prosthetic rehabilitation centres throughout the United States. METHODS: Oral administration of a brief assessment battery to 307 participants with ULL including demographic variables, injury information, screening instruments for PTSD and depression, pain interference, and activity restriction measures. Hierarchical multinomial logit models were conducted. Outcome groups were created using recommended cut-off scores on brief screening measures of depression and PTSD. Final models were assessed including relative risk ratios and marginal effects. RESULTS: Over half of the sample screened positive for depression, PTSD, or both. Eight individuals exceeded the recommended cut-off score indicative of PTSD only (2.6%), and 106 participants (34.5%) screened positive for depression only. Moreover, 64 participants (20.8%) reported co-occurring PTSD and depression. Subsequent models revealed women and ethnic minority participants were more likely to have clinically significant levels of depression and PTSD. Greater restriction in activity and increased pain interference also predicted psychological distress. CONCLUSIONS: These findings indicate a significant number of individuals with ULL experience clinically significant levels of psychological distress, and routine clinical assessment of depression and PTSD is warranted. Women and individuals from ethnic minorities may be particularly at risk, regardless of the severity and cause of ULL. Restrictions in preferred and goal-directed activities and persistent pain are also contributing factors. Psychological interventions that address these issues are indicated. Statement of contribution What is already known on this subject? Research investigating psychological reactions and adjustment after limb loss has primarily focused on lower limb loss. Little research has investigated psychological adjustment or distress following upper extremity loss. Lower extremity limb loss is more likely to be from a disease process while upper extremity limb loss is more likely to be due to traumatic injuries. Upper extremity limb loss possesses a qualitatively different experience as upper limb amputation is more readily apparent to others, impacts activities of daily living, and limits instrumental function in social and non-verbal communication. What does this study add? A significant percentage of individuals with upper limb loss report significant levels of depression, PTSD, and mixed depression and PTSD. Moreover, women and minority clients were more likely to report clinically significant levels of depression and mixed PTSD and depression. Activity restriction and pain interference’s contributions in the final model helped to elucidate the clinical picture of psychological distress for persons with upper extremity limb loss. Greater activity restriction and limitations from pain interference increased the likelihood of reporting clinically significant levels of psychological distress.

Alsahhar, J. S., D. Hansen, J. Page, U. Sandkovsky, S. Burdick, J. F. Trotter and R. S. Rahimi (2019). “An Atypical Biliary Fistula in a Liver Transplant Recipient.” Liver Transpl 25(4): 664-666.

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Biliary complications affect up to a third of patients after liver transplantation with bile leaks accounting for the majority of these complications. In this patient, we believe the fistula occurred as a complication of the second pericardiocentesis (likely intrahepatic puncture) because the initial pericardiocentesis resulted in drainage of bloody fluid. The exact etiology of the initial pericardial fluid is unknown despite the extensive infectious and rheumatologic workup. To our knowledge, this is the first case of a pericardiobiliary fistula reported as a complication of pericardiocentesis in a liver transplant recipient. There are 4 cases of pericardiobiliary fistula in the literature, 1 of which occurred after a liver biopsy, after penetrating abdominal trauma, and the last in the setting of an encroaching hydatid cyst. Our approach to managing this complication was with conservative measures using biliary stents to promote prograde biliary drainage along with infection control using antibiotics. This preferential flow of bile by using biliary stents promoted closure of the fistula and the prevention of surgery in a patient with a recent abdominal manipulation and medical instability. As the first reported case of pericardiobiliary fistula in a simultaneous liver‐kidney transplant recipient from pericardiocentesis, where no treatment or management has been reported, ERCP with stent placement can be considered for decompression. (Excerpt from text, p. 666; no abstract available.).

Garg, S. K., S. Sarvepalli, D. Singh, I. Obaitan, T. Peeraphatdit, L. Jophlin, S. K. Asrani, V. H. Shah and M. D. Leise (2019). “Incidence and Risk Factors Associated With 30-Day Readmission for Alcoholic Hepatitis.” J Clin Gastroenterol Apr 3. [Epub ahead of print].

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BACKGROUND: Alcohol abuse and liver disease are associated with high rates of 30-day hospital readmission, but factors linking alcoholic hepatitis (AH) to readmission are not well understood. We aimed to determine the incidence rate of 30-day readmission for patients with AH and to evaluate potential predictors of readmission. METHODS: We used the Nationwide Readmissions Database to determine the 30-day readmission rate for recurrent AH between 2010 and 2014 and examined trends in readmissions during the study period. We also identified the 20 most frequent reasons for readmission. Multivariate survey logistic regression analysis was used to identify factors associated with 30-day readmission. RESULTS: Of the 61,750 index admissions for AH, 23.9% were readmitted within 30-days. The rate of readmission did not change significantly during the study period. AH, alcoholic cirrhosis, and hepatic encephalopathy were the most frequent reasons for readmission. In multivariate analysis female sex, leaving against medical advice, higher Charlson comorbidity index, ascites, and history of bariatric surgery were associated with earlier readmissions, whereas older age, payer type (private or self-pay/other), and discharge to skilled nursing-facility reduced this risk. CONCLUSIONS: The 30-day readmission rate in patients with AH was high and stable during the study period. Factors associated with readmission may be helpful for development of consensus-based expert guidelines, treatment algorithms, and policy changes to help decrease readmission in AH.