Atrial Natriuretic Peptide Levels Reflect Hemodynamic Changes Under Pacemaker Stimulation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73244/1/j.1540-8159.1990.tb02142.x.pd

Myocardial ischemia with left ventricular outflow obstruction

We report an unusual case of a 32-year old man who was treated for a hypertrophic obstructive cardiomyopathy (HOCM) with a DDD pacing with short AV delay reduction in the past. Without prior notice the patient developed ventricular fibrillation and an invasive cardiac diagnostic was performed, which revealed a myocardial bridging around of the left anterior descending artery (LAD). We suspected ischemia that could be either related to LAD artery compression or perfusion abnormalities due to AV delay reduction with related to diastolic dysfunction

Coarse-Graining Protein Structures With Local Multivariate Features from Molecular Dynamics

A multivariate statistical theory, local feature analysis (LFA), extracts functionally relevant domains from molecular dynamics (MD) trajectories. The LFA representations, like those of principal component analysis (PCA), are low dimensional and provide a reduced basis set for collective motions of simulated proteins, but the local features are sparsely distributed and spatially localized, in contrast to global PCA modes. One key problem in the assignment of local features is the coarse-graining of redundant LFA output functions by means of seed atoms. One can solve the combinatorial problem by adding seed atoms one after another to a growing set, minimizing a reconstruction error at each addition. This allows for an efficient implementation, but the sequential algorithm does not guarantee the optimal mutual correlation of the sequentially assigned features. Here, we present a novel coarse-graining algorithm for proteins that directly minimizes the mutual correlation of seed atoms by Monte Carlo (MC) simulations. Tests on MD trajectories of two biological systems, bacteriophage T4 lysozyme and myosin II motor domain S1, demonstrate that the new algorithm provides statistically reproducible results and describes functionally relevant dynamics. The well-known undersampling of large-scale motion by short MD simulations is apparent also in our model, but the new coarse-graining offers a major advantage over PCA; converged features are invariant across multiple windows of the trajectory, dividing the protein into converged regions and a smaller number of localized, undersampled regions. In addition to its use in structure classification, the proposed coarse-graining thus provides a localized measure of MD sampling efficiency

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial

BACKGROUND: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. METHODS: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). INTERPRETATION: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR (RT-qPCR). Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC