TACAN Is an Ion Channel Involved in Sensing Mechanical Pain.

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.

Mortality predictions on admission as a context for organizing care activities.

BACKGROUND: Favorable health outcomes are more likely to occur when the clinical team recognizes patients at risk and intervenes in consort. Prediction rules can identify high-risk subsets, but the availability of multiple rules for various conditions present implementation and assimilation challenges. METHODS: A prediction rule for 30-day mortality at the beginning of the hospitalization was derived in a retrospective cohort of adult inpatients from a community hospital in the Midwestern United States from 2008 to 2009, using clinical laboratory values, past medical history, and diagnoses present on admission. It was validated using 2010 data from the same and from a different hospital. The calculated mortality risk was then used to predict unplanned transfers to intensive care units, resuscitation attempts for cardiopulmonary arrests, a condition not present on admission (complications), intensive care unit utilization, palliative care status, in-hospital death, rehospitalizations within 30 days, and 180-day mortality. RESULTS: The predictions of 30-day mortality for the derivation and validation datasets had areas under the receiver operating characteristic curve of 0.88. The 30-day mortality risk was in turn a strong predictor for in-hospital death, palliative care status, 180-day mortality; a modest predictor for unplanned transfers and cardiopulmonary arrests; and a weaker predictor for the other events of interest. CONCLUSIONS: The probability of 30-day mortality provides health systems with an array of prognostic information that may provide a common reference point for organizing the clinical activities of the many health professionals involved in the care of the patient.

Characterization of human embryonic stem cells with features of neoplastic progression.

Cultured human embryonic stem (hES) cells can acquire genetic and epigenetic changes that make them vulnerable to transformation. As hES cells with cancer-cell characteristics share properties with normal hES cells, such as self-renewal, teratoma formation and the expression of pluripotency markers, they may be misconstrued as superior hES cells with enhanced 'stemness'. We characterize two variant hES cell lines (v-hESC-1 and v-hESC-2) that express pluripotency markers at high levels and do not harbor chromosomal abnormalities by standard cytogenetic measures. We show that the two lines possess some features of neoplastic progression, including a high proliferative capacity, growth-factor independence, a 9- to 20-fold increase in frequency of tumor-initiating cells, niche independence and aberrant lineage specification, although they are not malignant. Array comparative genomic hybridization reveals an amplification at 20q11.1-11.2 in v-hESC-1 and a deletion at 5q34a-5q34b;5q3 and a mosaic gain of chromosome 12 in v-hESC-2. These results emphasize the need for functional characterization to distinguish partially transformed and normal hES cells.

Epithelial expression of profibrotic mediators in a model of allergen-induced airway remodeling.

Airway remodeling, including subepithelial fibrosis, is a characteristic feature of asthma and likely contributes to the pathogenesis of airway hyperresponsiveness. We examined expression of genes related to airway wall fibrosis in a model of chronic allergen-induced airway dysfunction using laser capture microdissection and quantitative real-time PCR. BALB/c mice were sensitized and subjected to chronic ovalbumin exposure over a 12-wk period, after which they were rested and then harvested 2 and 8 wk after the last exposure. Chronic allergen-exposed mice had significantly increased indices of airway remodeling and airway hyperreactivity at all time points, although no difference in expression of fibrosis-related genes was found when mRNA extracted from whole lung was examined. In contrast, fibrosis-related gene expression was significantly upregulated in mRNA obtained from microdissected bronchial wall at 2 wk after chronic allergen exposure. In addition, when bronchial wall epithelium and smooth muscle were separately microdissected, gene expression of transforming growth factor-beta1 and plasminogen activating inhibitor-1 were significantly upregulated only in the airway epithelium. These data suggest that transforming growth factor-beta1 and other profibrotic mediators produced by airway wall, and specifically, airway epithelium, play an important role in the pathophysiology of airway remodeling.

Improving quality of care for acute myocardial infarction: The Guidelines Applied in Practice (GAP) Initiative.

CONTEXT: Quality of care of patients with acute myocardial infarction (AMI) has received intense attention. However, it is unknown if a structured initiative for improving care of patients with AMI can be effectively implemented at a wide variety of hospitals. OBJECTIVE: To measure the effects of a quality improvement project on adherence to evidence-based therapies for patients with AMI. DESIGN AND SETTING: The Guidelines Applied in Practice (GAP) quality improvement project, which consisted of baseline measurement, implementation of improvement strategies, and remeasurement, in 10 acute-care hospitals in southeast Michigan. PATIENTS: A random sample of Medicare and non-Medicare patients at baseline (July 1998--June 1999; n = 735) and following intervention (September 1--December 15, 2000; n = 914) admitted at the 10 study centers for treatment of confirmed AMI. A random sample of Medicare patients at baseline (January--December 1998; n = 513) and at remeasurement (March--August 2001; n = 388) admitted to 11 hospitals that volunteered, but were not selected, served as a control group. INTERVENTION: The GAP project consisted of a kickoff presentation; creation of customized, guideline-oriented tools designed to facilitate adherence to key quality indicators; identification and assignment of local physician and nurse opinion leaders; grand rounds site visits; and premeasurement and postmeasurement of quality indicators. MAIN OUTCOME MEASURES: Differences in adherence to quality indicators (use of aspirin, beta-blockers, and angiotensin-converting enzyme [ACE] inhibitors at discharge; time to reperfusion; smoking cessation and diet counseling; and cholesterol assessment and treatment) in ideal patients, compared between baseline and postintervention samples and among Medicare patients in GAP hospitals and the control group. RESULTS: Increases in adherence to key treatments were seen in the administration of aspirin (81% vs 87%; P =.02) and beta-blockers (65% vs 74%; P =.04) on admission and use of aspirin (84% vs 92%; P =.002) and smoking cessation counseling (53% vs 65%; P =.02) at discharge. For most of the other indicators, nonsignificant but favorable trends toward improvement in adherence to treatment goals were observed. Compared with the control group, Medicare patients in GAP hospitals showed a significant increase in the use of aspirin at discharge (5% vs 10%; P<.001). Use of aspirin on admission, ACE inhibitors at discharge, and documentation of smoking cessation also showed a trend for greater improvement among GAP hospitals compared with control hospitals, although none of these were statistically significant. Evidence of tool use noted during chart review was associated with a very high level of adherence to most quality indicators. CONCLUSIONS: Implementation of guideline-based tools for AMI may facilitate quality improvement among a variety of institutions, patients, and caregivers. This initial project provides a foundation for future initiatives aimed at quality improvement.