Citations

Systemic insulin administration causes hypoaminoacidemia by inhibiting protein degradation, which may in turn inhibit muscle protein synthesis (PS). Insulin enhances muscle mitochondrial PS and ATP production when hypoaminoacidemia is prevented by exogenous amino acid (AA) replacement. We determined whether insulin would stimulate mitochondrial PS and ATP production in the absence of AA replacement. Using l-[1,2-13C]leucine as a tracer, we measured the fractional synthetic rate of mitochondrial as well as sarcoplasmic and mixed muscle proteins in 18 participants during sustained (7-h) insulin or saline infusion ( n = 9 each). We also measured muscle ATP production, mitochondrial enzyme activities, mRNA levels of mitochondrial genes, and phosphorylation of signaling proteins regulating protein synthesis. The concentration of circulating essential AA decreased during insulin infusion. Mitochondrial, sarcoplasmic, and mixed muscle PS rates were also lower during insulin (2–7 h) than during saline infusions despite increased mRNA levels of selected mitochondrial genes. Under these conditions, insulin did not alter mitochondrial enzyme activities and ATP production. These effects were associated with enhanced phosphorylation of Akt but not of protein synthesis activators mTOR, p70S6K, and 4EBP1. In conclusion, sustained physiological hyperinsulinemia without AA replacement did not stimulate PS of mixed muscle or protein subfractions and did not alter muscle mitochondrial ATP production in healthy humans. These results support that insulin and AA act in conjunction to stimulate muscle mitochondrial function and mitochondrial protein synthesis.

Background Do Not Resuscitate (DNR) orders are intended to safeguard patients' autonomy and prevent unwanted resuscitative care. However, DNR orders may be miscommunicated between health care providers, leading to errors honoring patient wishes during cardiac arrest events. This project focused on improving accuracy of DNR ordering processes for an academic, tertiary care hospital. Intervention We describe a performance improvement process and outcomes for implementation of an inpatient electronic ordering system that included an automated, decentralized printing process for resuscitation status armbands. Specific phases of this project involved: (a) identification of common factors contributing to errors honoring patients‘ resuscitation wishes, (b) design of an electronic ordering process, (c) design and integration of a new DNR armband and (d) evaluation of the impact of changes on communication accuracy. The primary outcome was percentage of patients with incorrect designation of resuscitation status on armbands compared to the active resuscitation order in the electronic medical record. Results After implementation of an electronic ordering process we identified that 37/196 (19%) patients had an armband that did not reflect their documented wishes versus 2/103 (2%) after integration of automated armband printing into the process (p<0.001). No armband discrepancies were found after the first two weeks of post-implementation audits. Conclusions Design and implementation of an electronic ordering and armband labeling process reduced discrepancies between patient wishes and the armband labeling of the patient's desired DNR status. It is anticipated that these improvements will reduce the risk of adverse outcomes, and better align clinical processes with patient wishes.

Survivors of breast cancer are faced with a multitude of medical and psychological impairments during and after treatment and throughout their lifespan. Physical exercise has been shown to improve survival and recurrence in this population. Mind-body interventions combine a light-moderate intensity physical exercise with mindfulness, thus having the potential to improve both physical and psychological sequelae of breast cancer treatments. We conducted a review of mindfulness-based physical exercise interventions which included yoga, tai chi chuan, Pilates, and qigong, in breast cancer survivors. Among the mindfulness-based interventions, yoga was significantly more studied in this population as compared to tai chi chuan, Pilates, and qigong. The participants and the outcomes of the majority of the studies reviewed were heterogeneous, and the population included was generally not selected for symptoms. Yoga was shown to improve fatigue in a few methodologically strong studies, providing reasonable evidence for benefit in this population. Improvements were also seen in sleep, anxiety, depression, distress, quality of life, and postchemotherapy nausea and vomiting in the yoga studies. Tai chi chuan, Pilates, and qigong were not studied sufficiently in breast cancer survivors in order to be implemented in clinical practice.

AbstractGenetic aberrations, including trisomies 3 and 18, and well-defined IGH translocations, have been described in marginal zone lymphomas (MZLs); however, these known genetic events are present in only a subset of cases. Here, we report the cloning of an IGH translocation partner on chromosome X, t(X;14)(p11.4;q32) that deregulates expression of an poorly characterized orphan G-protein–coupled receptor, GPR34. Elevated GPR34 gene expression was detected independent of the translocation in multiple subtypes of non-Hodgkin lymphoma and distinguished a unique molecular subtype of MZL. Increased expression of GPR34 was also detected in tissue from brain tumors and surface expression of GPR34 was detected on human MZL tumor cells and normal immune cells. Overexpression of GPR34 in lymphoma and HeLa cells resulted in phosphorylation of ERK, PKC, and CREB; induced CRE, AP1, and NF-κB–mediated gene transcription; and increased cell proliferation. In summary, these results are the first to identify a role for a GPR34 in lymphoma cell growth, provide insight into GPR34-mediated signaling, identify a genetically unique subset of MZLs that express high levels of GPR34, and suggest that MEK inhibitors may be useful for treatment of GPR34-expressing tumors.

While it is evident that the carboxyl‐terminal region of natural peptide ligands bind to the amino‐terminal domain of class B GPCRs, how their biologically critical amino‐terminal regions dock to the receptor is unclear. We utilize cysteine trapping to systematically explore spatial approximations among residues in the first five positions of secretin and in every position within the receptor extracellular loops (ECLs). Only Cys 2 and Cys 5 secretin analogues exhibited full activity and retained moderate binding affinity (IC 50 : 92±4 and 83±1 nM, respectively). When these peptides probed 61 human secretin receptor cysteine‐replacement mutants, a broad network of receptor residues could form disulfide bonds consistent with a dynamic ligand‐receptor interface. Two distinct patterns of disulfide bond formation were observed: Cys 2 predominantly labeled residues in the amino terminus of ECL2 and ECL3 (relative labeling intensity: Ser 340 , 94±7%; Pro 341 , 84±9%; Phe 258 , 73±5%; Trp 274 62±8%), and Cys 5 labeled those in the carboxyl terminus of ECL2 and ECL3 (Gln 348 , 100%; Ile 347 , 73±12%; Glu 342 , 59±10%; Phe 351 , 58±11%). These constraints were utilized in molecular modeling, providing improved understanding of the structure of the transmembrane bundle and interconnecting loops, the orientation between receptor domains, and the molecular basis of ligand docking. Key spatial approximations between peptide and receptor predicted by this model (H 1 ‐W 274 , D 3 ‐N 268 , G 4 ‐F 258 ) were supported by mutagenesis and residue‐residue complementation studies.—Dong, M., Xu, X., Ball, A. M., Makhoul, J. A., Lam, P. C.‐H., Pinon, D. I., Orry, A., Sexton, P. M., Abagyan, R., Miller, L. J. Mapping spatial approximations between the amino terminus of secretin and each of the extracellular loops of its receptor using cysteine trapping. FASEB J. 26, 5092–5105 (2012). www.fasebj.org

Anticholinergics, or antimuscarinic drugs, are drugs that competitively inhibit the action of acetylcholine at muscarinic receptors, leading to a blockade of the actions of the parasympathetic nervous system at sites where overactivity can lead to increased symptom burden. Successful blockade of the parasympathetic nervous system ultimately leads to decreased production of secretions in the salivary, bronchial, and gastrointestinal tracts. These effects are often used for several symptoms that originate due to parasympathetic nervous system overactivity, such as the “death rattle” and malignant bowel obstruction. Anticholinergic agents are divided into either tertiary amines or quaternary ammonium compounds, which differ in their ability to cross into the central nervous system. Quaternary compounds do not cross into the central nervous system and have a different adverse effect profile than the tertiary amines. The purpose of this review is to highlight anticholinergic agents, their pharmacology, and an evidence-based assessment of their role in palliative care.

Background— The importance of complete revascularization remains unclear and contradictory. This current investigation compares the effect of complete revascularization on 10-year survival of patients with stable multivessel coronary artery disease (CAD) who were randomly assigned to percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Methods and Results— This is a post hoc analysis of the Second Medicine, Angioplasty, or Surgery Study (MASS II), which is a randomized trial comparing treatments in patients with stable multivessel CAD, and preserved systolic ventricular function. We analyzed patients who underwent surgery (CABG) or stent angioplasty (PCI). The survival free of overall mortality of patients who underwent complete (CR) or incomplete revascularization (IR) was compared. Of the 408 patients randomly assigned to mechanical revascularization, 390 patients (95.6%) underwent the assigned treatment; complete revascularization was achieved in 224 patients (57.4%), 63.8% of those in the CABG group and 36.2% in the PCI group ( P =0.001). The IR group had more prior myocardial infarction than the CR group (56.2%×39.2%, P =0.01). During a 10-year follow-up, the survival free of cardiovascular mortality was significantly different among patients in the 2 groups (CR, 90.6% versus IR, 84.4%; P =0.04). This was mainly driven by an increased cardiovascular specific mortality in individuals with incomplete revascularization submitted to PCI ( P =0.05). Conclusions— Our study suggests that in 10-year follow-up, CR compared with IR was associated with reduced cardiovascular mortality, especially due to a higher increase in cardiovascular-specific mortality in individuals submitted to PCI. Clinical Trial Registration Information— URL: http://www.controlled-trials.com . Registration number: ISRCTN66068876.

Breast cancer is the most common malignancy among women in the United States with the second highest incidence of cancer-related death following lung cancer. The decision-making process regarding adjuvant therapy is a time intensive dialogue between the patient and her oncologist. There are multiple tools that help individualize the treatment options for a patient. Population-based analysis with Adjuvant! Online and genomic profiling with Oncotype DX are two commonly used tools in patients with early stage, node-negative breast cancer. This case report illustrates a situation in which the population-based prognostic and predictive information differed dramatically from that obtained from genomic profiling and affected the patient’s decision. In light of this case, we discuss the benefits and limitations of these tools.