Glycogenin is Dispensable for Glycogen Synthesis in Human Muscle, and Glycogenin Deficiency Causes Polyglucosan Storage

Glycogenin is considered to be an essential primer for glycogen biosynthesis. Nevertheless, patients with glycogenin-1 deficiency due to biallelic GYG1 (NM_004130.3) mutations can store glycogen in muscle. Glycogenin-2 has been suggested as an alternative primer for glycogen synthesis in patients with glycogenin-1 deficiency. OBJECTIVE: The objective of this article is to investigate the importance of glycogenin-1 and glycogenin-2 for glycogen synthesis in skeletal and cardiac muscle. DESIGN, SETTING, AND PATIENTS: Glycogenin-1 and glycogenin-2 expression was analyzed by Western blot, mass spectrometry, and immunohistochemistry in liver, heart, and skeletal muscle from controls and in skeletal and cardiac muscle from patients with glycogenin-1 deficiency. RESULTS: Glycogenin-1 and glycogenin-2 both were found to be expressed in the liver, but only glycogenin-1 was identified in heart and skeletal muscle from controls. In patients with truncating GYG1 mutations, neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, nonfunctional glycogenin-1 but not glycogenin-2 was identified in cardiac muscle from patients with cardiomyopathy due to GYG1 missense mutations. By immunohistochemistry, the mutated glycogenin-1 colocalized with the storage of glycogen and polyglucosan in cardiomyocytes. CONCLUSIONS: Glycogen can be synthesized in the absence of glycogenin, and glycogenin-1 deficiency is not compensated for by upregulation of functional glycogenin-2. Absence of glycogenin-1 leads to the focal accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of mutated glycogenin-1 in the heart is deleterious, and it leads to storage of abnormal glycogen and cardiomyopathy

Serum biomarkers of brain injury after uncomplicated cardiac surgery: Secondary analysis from a randomized trial

BACKGROUND: Postoperative cognitive dysfunction is common after cardiac surgery. Postoperative measurements of brain injury biomarkers may identify brain damage and predict cognitive dysfunction. We describe the release patterns of five brain injury markers in serum and plasma after uncomplicated cardiac surgery. METHODS: Sixty-one elective cardiac surgery patients were randomized to undergo surgery with either a dextran-based prime or a crystalloid prime. Blood samples were taken immediately before surgery, and 2 and 24 hours after surgery. Concentrations of the brain injury biomarkers S100B, glial fibrillary acidic protein (GFAP), tau, neurofilament light (NfL) and neuron-specific enolase (NSE)) and the blood-brain barrier injury marker β-trace protein were analyzed. Concentrations of brain injury biomarkers were correlated to patients' age, operation time, and degree of hemolysis. RESULTS: No significant difference in brain injury biomarkers was observed between the prime groups. All brain injury biomarkers increased significantly after surgery (tau +456% (25th-75th percentile 327%-702%), NfL +57% (28%-87%), S100B +1145% (783%-2158%), GFAP +17% (-3%-43%), NSE +168% (106%-228%), while β-trace protein was reduced (-11% (-17-3%). Tau, S100B and NSE peaked at 2h, NfL and GFAP at 24h. Postoperative concentrations of brain injury markers correlated to age, operation time, and/or hemolysis. CONCLUSION: Uncomplicated cardiac surgery with cardiopulmonary bypass is associated with an increase in serum/plasma levels of all the studied injury markers, without signs of blood-brain barrier injury. The biomarkers differ markedly in their levels of release and time course. Further investigations are required to study associations between perioperative release of biomarkers, postoperative cognitive function and clinical outcome

Urgent lung allocation system in the Scandiatransplant countries

BACKGROUND: Throughout the world, the scarcity of donor organs makes optimal allocation systems necessary. In the Scandiatransplant countries, organs for lung transplantation are allocated nationally. To ensure shorter wait time for critically ill patients, the Scandiatransplant urgent lung allocation system (ScULAS) was introduced in 2009, giving supranational priority to patients considered urgent. There were no pre-defined criteria for listing a patient as urgent, but each center was granted only 3 urgent calls per year. This study aims to explore the characteristics and outcome of patients listed as urgent, assess changes associated with the implementation of ScULAS, and describe how the system was utilized by the member centers. METHODS: All patients listed for lung transplantation at the 5 Scandiatransplant centers 5 years before and after implementation of ScULAS were included. RESULTS: After implementation, 8.3% of all listed patients received urgent status, of whom 81% were transplanted within 4 weeks. Patients listed as urgent were younger, more commonly had suppurative lung disease, and were more often on life support compared with patients without urgent status. For patients listed as urgent, post-transplant graft survival was inferior at 30 and 90 days. Although there were no pre-defined criteria for urgent listing, the system was not utilized at its maximum. CONCLUSIONS: ScULAS rapidly allocated organs to patients considered urgent. These patients were younger and more often had suppurative lung disease. Patients with urgent status had inferior short-term outcome, plausibly due to the higher proportion on life support before transplantation. (C) 2018 International Society for Heart and Lung Transplantation. All rights reserved.Peer reviewe

Life Expectancy After Surgical Aortic Valve Replacement.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBackground: Surgical risk, age, perceived life expectancy, and valve durability influence the choice between surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation. The contemporaneous life expectancy after SAVR, in relation to surgical risk and age, is unknown. Objectives: The purpose of this study was to determine median survival time in relation to surgical risk and chronological age in SAVR patients. Methods: Patients ≥60 years with aortic stenosis who underwent isolated SAVR with a bioprosthesis (n = 8,353) were risk-stratified before surgery into low, intermediate, or high surgical risk using the logistic EuroSCORE (2001-2011) or EuroSCORE II (2012-2017) and divided into age groups. Median survival time and cumulative 5-year mortality were estimated with Kaplan-Meier curves. Cox regression analysis was used to further determine the importance of age. Results: There were 7,123 (85.1%) low-risk patients, 942 (11.3%) intermediate-risk patients, and 288 (3.5%) high-risk patients. Median survival time was 10.9 years (95% confidence interval: 10.6-11.2 years) in low-risk, 7.3 years (7.0-7.9 years) in intermediate-risk, and 5.8 years (5.4-6.5 years) in high-risk patients. The 5-year cumulative mortality was 16.5% (15.5%-17.4%), 30.7% (27.5%-33.7%), and 43.0% (36.8%-48.7%), respectively. In low-risk patients, median survival time ranged from 16.2 years in patients aged 60 to 64 years to 6.1 years in patients aged ≥85 years. Age was associated with 5-year mortality only in low-risk patients (interaction P < 0.001). Conclusions: Eighty-five percent of SAVR patients receiving bioprostheses have low surgical risk. Estimated survival is substantial following SAVR, especially in younger, low-risk patients, which should be considered in Heart Team discussions. Keywords: aortic stenosis; aortic valve replacement; epidemiology; valvular heart disease.Swedish Heart-Lung Foundation Swedish government Swedish county councils concerning economic support of research and education of doctors (ALF agreement) ALFGBG-725131 Vastra Gotaland Region Family Nils Winberg's Foundatio

Altered regulation and expression of genes by BET family of proteins in COPD patients

Correction: PLoS One 2018 12 (4): 0175997Background BET proteins (BRD2, BRD3, BRDT and BRD4) belong to the family of bromodomain containing proteins, which form a class of transcriptional co-regulators. BET proteins bind to acetylated lysine residues in the histones of nucleosomal chromatin and function either as co-activators or co-repressors of gene expression. An imbalance between HAT and HDAC activities resulting in hyperacetylation of histones has been identified in COPD. We hypothesized that pan-BET inhibitor (JQ1) treatment of BET protein interactions with hyperacety-lated sites in the chromatin will regulate excessive activation of pro-inflammatory genes in key inflammatory drivers of alveolar macrophages (AM) in COPD. Methods and findings Transcriptome analysis of AM from COPD patients indicated up-regulation of macrophage M1 type genes upon LPS stimulation. Pan-BET inhibitor JQ1 treatment attenuated expression of multiple genes, including pro-inflammatory cytokines and regulators of innate and adaptive immune cells. We demonstrated for the first time that JQ1 differentially modulated LPS-induced cytokine release from AM or peripheral blood mononuclear cells (PBMC) of COPD patients compared to PBMC of healthy controls. Using the BET regulated gene signature, we identified a subset of COPD patients, which we propose to benefit from BET inhibition. Conclusions This work demonstrates that the effects of pan-BET inhibition through JQ1 treatment of inflammatory cells differs between COPD patients and healthy controls, and the expression of BET protein regulated genes is altered in COPD. These findings provide evidence of histone hyperacetylation as a mechanism driving chronic inflammatory changes in COPD.Peer reviewe

Pediatric heart transplantation: Improving results in high-risk patients

AbstractObjectives: Our institutional experience with 73 pediatric patients undergoing cardiac transplantation between January 1, 1990, and December 31, 1999, was reviewed to determine the impact of unconventional donor and recipient management protocols implemented to extend the availability of this therapy. Methods and results: The introduction of donor blood cardioplegic solution with added insulin was associated with a significant improvement in patient and graft survival (hazard ratio [Cox] = 0.25, P =.08), despite significantly longer ischemic times with this protocol compared with the use of crystalloid-based donor procurement techniques (P <.01). Eleven patients underwent intentional transplantation of ABO-incompatible donor hearts with the aid of a protocol of plasma exchange on bypass. In this subgroup, there were 2 early deaths caused by nonspecific graft failure (n = 1) and respiratory complications with mild vascular rejection (n = 1), and there was 1 late death caused by lymphoma. ABO-incompatible transplantation was not a risk factor for death by multivariate analysis. The postoperative course in these patients suggests minimal reactivity directed against incompatible grafts on the basis of low anti-donor blood group antibody production, in association with a favorable rejection profile. Ten of 13 patients requiring preoperative support with an extracorporeal membrane oxygenator survived transplantation; there were 3 additional late deaths in this subgroup (hazard ratio = 2.88, P =.05). Conclusions: The results with pediatric cardiac transplantation continue to improve as a result of changes in both surgical and medical protocols permitting successful treatment of patients conventionally considered at high risk or unsuitable for transplantation. (J Thorac Cardiovasc Surg 2001;121:782-91

Aortic valve replacement with stentless bioprostheses : Prospective long-term studies of the Biocor and the Toronto SPV

Background. Aortic valve disease is increasing among the elderly and aortic valve replacement is the most common cardiac surgical valve procedure in adults. Aortic stenosis (AS) is often associated with left ventricular hypertrophy (LVH) in an unexplained pattern. Traditionally, younger patients receive mechanical valves and patients older than 70 years receive bioprostheses. Stentless bioprostheses have physiologically attractive hemodynamic properties. There is hope that stentless bioprostheses will improve long-term survival and that a reduced risk of valve-related complications will allow its use in younger patients than those receiving bioprostheses today. Patients and methods. These studies comprise 367 patients operated with the Biocor stentless (BS, n= 112) or the Toronto stentless porcine valve (T-SPV, n=255) bioprostheses in two different patient populations (mean age; 78.5 vs. 63.3 years and female; 66% vs. 29%, respectively). Early and late clinical results were evaluated for both patient populations. Long-term survival for the BS population was compared to expected survival for an age- and gender-matched comparison population and relative survival rates were calculated. Hemodynamic results were investigated by echocardiography for both valves at early and late follow-up, and in addition, the BS valve was evaluated during exercise. Regression of left ventricular mass index (LVMI) was studied in both populations after the use of stentless bioprostheses. The angiotensin-converting enzyme (ACE) gene insertion (1) / deletion (D) polymorphism was studied and subsequently related to LVMI in patients with AS operated with stentless valves. Results. Early mortality was 7% (81112) and 1% (21255) for the BS and the T-SPV valve groups, respectively, and long-term actuarial survival at 7 years was 59%±6% and 90%±2%. There was no difference in survival between the BS valve patients and the expected survival for the age- and gender- matched comparison population supplied by Statistics Sweden, and the annual relative survival rates indicated a normalized survival pattern for those patients. Valve-related complications were few for both stentless valves under study. Early and late hemodynamic function was similar and at seven years the mean pressure difference across the aortic valve was 5.4±2.0 and 3.6±2.0 mm Hg for the BS and the T-SPV valves, respectively. Coronary artery disease and hypertension were associated with a higher LVMI over time in patients with the T-SPV and most patients had a normal LVMI at five years of follow-up. Patients with the DD genotype of the ACE gene had a higher LVMI (197±47g/m2) preoperatively than those with ID (175±41g/m2) or H (155±43 g/m2) genotypes (p=0.01). The left ventricular mass index decreased in DD (p<0.001) and ID (p<0.001) genotypes but not in the H genotype during follow-up. There was a significant difference in regression of LVMI over time between genotypes (p=0.0056) with no significant difference between genotypes at follow-up. Conclusions. Early and long-term hemodynamic function is excellent for both stentless bioprostheses and they both confer good long-term survival. The BS patient population could be regarded as "cured" from valve disease since the observed survival did not differ from the expected survival for an ageand gender-matched Swedish comparison population, a conclusion that is also supported by a constant relative survival after the first postoperative year. Coronary artery disease and hypertension influenced the degree of LVH and its regression over time and most patients with the T-SPV valve had no LVH at long-term follow-up. Furthermore, I/D polymorphism of the ACE gene is one determinant for the hypertrophic response in patients with severe AS

The trajectory of renal function following mechanical circulatory support and subsequent heart transplantation

Abstract Aim Patients with advanced heart failure (HF) frequently suffer from renal insufficiency. The impact of durable mechanical circulatory support (MCS) and subsequent heart transplantation (HTx) on kidney function is not well described. Methods and results We studied patients with advanced HF who received durable MCS as bridge to transplantation (BTT) and underwent subsequent HTx at our centre between 1996 and 2018. Glomerular filtration rate (GFR) was measured by 51Cr‐EDTA or iohexol clearance during heart failure work‐up; 3–6 months after MCS; and 1 year after HTx. Chronic kidney disease (CKD) was classified according to KDIGO criteria based on estimated GFR. A total of 88 patients (46 ± 15 years, 84% male) were included, 63% with non‐ischaemic heart disease. The median duration of MCS‐treatment was 172 (IQR 116–311) days, and 81 subjects were alive 1 year after HTx. Measured GFR increased from 54 ± 19 during HF work‐up to 60 ± 16 mL/min/1.73 m2 after MCS (P < 0.001) and displayed a slight but nonsignificant decrease to 57 ± 22 mL/min/1.73 m2 1 year after HTx (P = 0.38). The trajectory of measured GFR did not differ between pulsatile and continuous flow (CF) pumps. Among patients 35–49 years and those who were treated in the most recent era (2012–2018), measured GFR increased following MCS implantation and subsequent HTx. Estimated GFR displayed a similar course as did measured GFR. Conclusions In patients with advanced heart failure, measured GFR improved after MCS with no difference between pulsatile and CF‐pumps. The total study group showed no further increase in GFR following HTx, but in certain subgroups, including patients aged 35–54 years and those treated during the latest era (2012–2018), renal function appeared to improve after transplant