Surviving cardiac arrest from severe metformin-associated lactic acidosis using extracorporeal membrane oxygenation and double continuous venovenous haemodialysis.

Metformin-associated lactic acidosis (MALA) is a serious condition with high mortality. This case describes a man in the mid-60s with diabetes mellitus type 2 treated with metformin developing MALA 4 days after coronary stenting for non-ST-elevation myocardial infarction. He presented acutely with severe abdominal pain, a lactate of 19 mmol/L and pH 6.74. Despite treatment for MALA, he went into refractory cardiac arrest and was connected to venoarterial extracorporeal membrane oxygenation (VA-ECMO). He suffered a massive haemothorax due to perforation of the right atrial appendage. It was repaired through a sternotomy while being given massive blood transfusions. The following days, he was on VA-ECMO and double continuous venovenous haemodialysis (CVVHD). He survived with only mild paresis of the left hand. VA-ECMO should be considered a rescue therapy alongside treatment with CVVHD in case of cardiac arrest due to severe MALA.

Comparison of Survival After Aortic Valve Replacement With Mitroflow or Perimount Prostheses.

Bioprosthetic aortic valves degenerate over time, and differences between brands could be expected. We compared 2 brands implanted in 3 different centers serving 3.3 million people. Between 2000 and 2014, we identified 1241 bioprosthetic aortic valve replacements using Mitroflow (Sorin, Milan, Italy) and 3212 using Perimount (Edwards Lifesciences, Irvine, CA) covering 88% of all aortic valve replacements in the region. Average differences in t-year mortality were derived from Cox regression. The complete case analyses included 881 Mitroflow replacements and 2488 Perimount replacements. The median follow-up time and 25/75 percentiles were 5.0 years (3.3-7.2) and 8.4 years (5.1-10.6) for Perimount and Mitroflow, respectively. Multiple Cox regression analyses demonstrated significantly higher mortality with Mitroflow valves compared with Perimount (hazard ratio 1.27; 95% CI: 1.1-1.5; P < 0.001). Average risk of death within 5 years was 25.0% with Mitroflow and 20.4% with Perimount. Average difference in 5-year mortality based on Cox regression was 4.60% in favor of Perimount (95% CI: 1.02-8.02%; P = 0.01) and the number needed to harm was 21.9 (95% CI: 12.7-80.5) within 5 years. Propensity matching confirmed 2-year survival differences 4.6% in favor of Perimount (95% CI: 1.2-7.9%; P = 0.004), and further confirmed in a series of subgroups and a double robust analysis that takes into account both propensity for treatment and covariate relation to outcome. Mitroflow valves were associated with a significantly increased risk of death when compared to Perimount valves.

A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis.

Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients' myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM.

Structural valve deterioration in the Mitroflow biological heart valve prosthesis.

OBJECTIVES: Concern has been raised regarding the long-term durability of the Mitroflow biological heart valve prosthesis. Our aim was to assess the incidence of structural valve degeneration (SVD) for the Mitroflow bioprosthesis in a nationwide study in Denmark including all patients alive in Denmark who had received a Mitroflow aortic bioprosthesis since 2000. METHODS: Patients alive in Denmark with a Mitroflow bioprosthesis implanted since January 2000 were invited to participate in a nationwide cross-sectional study with a predefined definition of SVD. Of 1552 patients, 861 patients had died and 47 patients had been reoperated with 40 reoperations due to SVD. The remaining 644 patients were invited for evaluation; 574 patients accepted and were evaluated for SVD. The incidence of SVD was calculated using competing risk regression analysis with death as the competing event. RESULTS: A total of 173 patients were diagnosed with SVD by echocardiography. Of these, 64 (11%) patients had severe SVD and 109 (19%) patients moderate SVD. Severe SVD was associated with the age of the prosthesis and small prosthesis size [Size 21: hazard ratio (95% confidence interval, CI) 2.72 (0.97-8.56), P = 0.06; Size 19: 6.26 (1.63-24.06), P = 0.008]. The cumulative incidences of reoperation or severe SVD at Year 9 were 12.5% for Size 19, 7.6% for Size 21 and 3.1 (1.2-6.4)% for Size 23. Median survival in patients with prosthesis Sizes 23-29 was 6.4 (95% CI 5.7-7.0) years, with Size 21 it was 6.5 (95% CI 5.9-7.1) years and with Size 19 it was 6.9 (95% CI 5.7-8.2) years (P = 0.78). CONCLUSIONS: The incidence of undetected severe SVD was as high as the incidence of operated SVD. The overall risk for SVD is high for the Mitroflow bioprosthesis, especially if the prosthesis is small and older than 5 years.

Characterization of memory B cells from thymus and its impact for DLBCL classification.

The rare memory B cells in thymus (Thy) are considered the cells of origin for primary mediastinal large B-cell lymphoma. The objectives of the present study were to characterize the normal memory B-cell compartment in Thy and to support its association with primary mediastinal B-cell lymphoma. Seven paired human tissue samples from Thy and sternum bone marrow (BM) were harvested during cardiac surgery. B-cell subsets were phenotyped by Euroflow standard and fluorescence-activated cell sorting for microarray analysis on the Human Exon 1.0 ST Arrays platform. Differentially expressed genes between Thy and BM memory B cells were identified and correlated with the molecular subclasses of diffuse large B-cell lymphoma. Within Thy, 4% (median; range 2%-14%) of the CD45(+) hematopoietic cells were CD19(+) B cells, with a major fraction being CD27(+)/CD38(-) memory B cells (median 80%, range 76%-93%). The BM contained 14% (median; range 3%-27%), of which only a minor fraction (median 5%, range 2%-10%) were memory B cells. Global gene expression analysis of the memory B-cell subsets from the two compartments identified 133 genes upregulated in Thy, including AICDA, REL, STAT1, TNF family, SLAMF1, CD80, and CD86. In addition, exons 4 and 5 in the 3' end of AICDA were more highly expressed in Thy than in BM. The Thy memory B-cell gene profile was overexpressed in primary mediastinal B-cell lymphoma compared with other diffuse large B-cell lymphoma subclasses. The present study describes a Thy memory B-cell subset and its gene profile correlated with primary mediastinal B-cell lymphomas, suggesting origin from Thy memory B cells.

Ibuprofen - a Safe Analgesic During Cardiac Surgery Recovery? A Randomized Controlled Trial.

INTRODUCTION: Postoperative pain-management with non-steroid anti-inflammatory drugs has been controversial, due to related side-effects. We investigated whether there was a significant difference between an oxycodone-based pain-management regimen versus a slow-release ibuprofen based regimen, in a short term post-cardiac surgery setting. Particular attention was given to the rate of myocardial infarction, sternal healing, gastro-intestinal complications, renal failure and all-cause mortality. METHODS: This was a single-centre, open label parallel design randomised controlled study. Patients, who were undergoing cardiac surgery for the first time, were randomly allocated either to a regimen of slow-release oxycodone (10 mg twice daily) or slow-release ibuprofen (800 mg twice daily) combined with lansoprazole. Data relating to blood-tests, angiographies, surgical details and administered medicine were obtained from patient records. The follow-up period was 1 to 37 months (median 25 months). RESULTS: One hundred eighty-two patients were included in the trial and available for intention to treat analysis. There were no significant difference between the groups (P>0.05) in the rates of sternal healing, postoperative myocardial infarction or gastrointestinal bleeding. The preoperative levels of creatinine were found to increase by 100% in nine patients (9.6%) in the ibuprofen group, resulting in an acute renal injury (in accordance with the RIFLE-criteria). Eight of these patients returned to normal renal function within 14 days. The levels of creatinine in patients in the oxycodone group were not found to increase to the same magnitude. CONCLUSION: The results of this study suggest that patients treated postoperatively, following cardiac surgery, are at no greater risk of harm if short term slow release ibuprofen combined with lansoprazole treatment is used when compared to an oxycodone based regimen. Renal function should, however, be closely monitored and in the event of any decrease in renal function ibuprofen must be discontinued.

Work Status and Return to the Workforce after Coronary Artery Bypass Grafting and/or Heart Valve Surgery: A One-Year-Follow Up Study.

Background. Several characteristics appear to be important for estimating the likelihood of reentering the workforce after surgery. The aim of the present study was to describe work status in a two-year time period around the time of cardiac surgery and estimate the probability of returning to the workforce. Methods. We included 681 patients undergoing coronary artery bypass grafting and/or heart valve procedures from 2003 to 2007 in the North Denmark Region. We linked hospital data to data in the DREAM database which holds information of everyone receiving social benefits. Results. At the time of surgery 17.3% were allocated disability pension and 2.3% were allocated a permanent part-time benefit. Being unemployed one year before surgery reduced the likelihood of return to the workforce (RR = 0.74 (0.60-0.92)) whereas unemployment at the time of surgery had no impact on return to the workforce (RR = 0.96 (0.78-1.18)). Sickness absence before surgery reduced the likelihood of return to the workforce. Conclusion. This study found the work status before surgery to be associated with the likelihood of return to the workforce within one year after surgery. Before surgery one-fifth of the population either was allocated disability pension or received a permanent part-time benefit.

Validation and implementation of a method for microarray gene expression profiling of minor B-cell subpopulations in man.

BACKGROUND: This report describes a method for the generation of global gene expression profiles from low frequent B-cell subsets by using fluorescence-activated cell sorting and RNA amplification. However, some of the differentiating compartments involve a low number of cells and therefore it is important to optimize and validate each step in the procedure. METHODS: Normal lymphoid tissues from blood, tonsils, thymus and bone marrow were immunophenotyped by the 8-colour Euroflow panel using multiparametric flow cytometry. Subsets of B-cells containing cell numbers ranging from 800 to 33,000 and with frequencies varying between 0.1 and 10 percent were sorted, subjected to mRNA purification, amplified by the NuGEN protocol and finally analysed by the Affymetrix platform. RESULTS: Following a step by step strategy, each step in the workflow was validated and the sorting/storage conditions optimized as described in this report. First, an analysis of four cancer cell lines on Affymetrix arrays, using either 100 ng RNA labelled with the Ambion standard protocol or 1 ng RNA amplified and labelled by the NuGEN protocol, revealed a significant correlation of gene expressions (r ≥ 0.9 for all). Comparison of qPCR data in samples with or without amplification for 8 genes showed that a relative difference between six cell lines was preserved (r ≥ 0.9). Second, a comparison of cells sorted into PrepProtect, RNAlater or directly into lysis/binding buffer showed a higher yield of purified mRNA following storage in lysis/binding buffer (p < 0.001). Third, the identity of the B-cell subsets validated by the cluster of differentiation (CD) membrane profile was highly concordant with the transcriptional gene expression (p-values <0.001). Finally, in normal bone marrow and tonsil samples, eight evaluated genes were expressed in accordance with the biology of lymphopoiesis (p-values < 0.001), which enabled the generation of a gene-specific B-cell atlas. CONCLUSION: A description of the implementation and validation of commercially available kits in the laboratory has been examined. This included steps for cell sorting, cell lysis/stabilization, RNA isolation, RNA concentration and amplification for microarray analysis. The workflow described in this report will enable the generation of microarray data from minor sorted B-cell subsets.

Cell of origin associated classification of B-cell malignancies by gene signatures of the normal B-cell hierarchy.

Recent findings have suggested biological classification of B-cell malignancies as exemplified by the "activated B-cell-like" (ABC), the "germinal-center B-cell-like" (GCB) and primary mediastinal B-cell lymphoma (PMBL) subtypes of diffuse large B-cell lymphoma and "recurrent translocation and cyclin D" (TC) classification of multiple myeloma. Biological classification of B-cell derived cancers may be refined by a direct and systematic strategy where identification and characterization of normal B-cell differentiation subsets are used to define the cancer cell of origin phenotype. Here we propose a strategy combining multiparametric flow cytometry, global gene expression profiling and biostatistical modeling to generate B-cell subset specific gene signatures from sorted normal human immature, naive, germinal centrocytes and centroblasts, post-germinal memory B-cells, plasmablasts and plasma cells from available lymphoid tissues including lymph nodes, tonsils, thymus, peripheral blood and bone marrow. This strategy will provide an accurate image of the stage of differentiation, which prospectively can be used to classify any B-cell malignancy and eventually purify tumor cells. This report briefly describes the current models of the normal B-cell subset differentiation in multiple tissues and the pathogenesis of malignancies originating from the normal germinal B-cell hierarchy.

The outcome of sternal wire removal on persistent anterior chest wall pain after median sternotomy.

OBJECTIVE: To evaluate the effect of wire removal on a consecutive series of patients with persistent anterior chest wall pain after median sternotomy. METHODS: Ninety-five patients receiving sternal wire removal during the period January 1994-October 2001 were included in a follow-up study. Preoperative data, data from the primary operation, the postoperative course, and the sternal wire removal were collected from patient histories. The patients were attempted contacted by telephone, and interviewed about the outcome of the wire removal. RESULTS: Wire removals were performed 2.7+/-3.3 (SD) years (40 days-20 years) after the primary procedure. Wire removal appeared to occur more frequently in patients with allergies, patients receiving valve-related procedures, and patients that had been reoperated for surgical complications within the first month after the primary operation. In 79 patients, the pain was unrelated to skin affection or infection. Full follow-up was available for 71 patients. For 24 patients only partial follow-up was possible since the patients were dead (n = 19) or unreachable (n = 5). Of the patients followed up, 86% reported complete or partial relief of symptoms, while 11% reported no change in symptoms, and 3% reported worsening of symptoms after wire removal. In patients (n = 23) where symptoms appeared to be related to specific wires, only these were removed, and this approach produced as good results as for patients where all wires were removed. CONCLUSIONS: The surgical results were generally good. Sternal wire removal should be offered to patients with persistent anterior chest wall pain after sternotomy, when other serious postoperative complications have been excluded.