Three tests of the hypothesis that glutamate is the sensory hair cell transmitter in the frog semicircular canal

Three series of experiments were devised to test the hypothesis that glutamate is the transmitter released by sensory hair cells of the frog semicircular canal. These three tests were: 1 - The Tolerance experiment (i.e. making the preparation tolerant to injected Glu yet still capable of responding to endogenous transmitter). 2 - The Glu Decarboxylase experiment (i.e. bathing the preparation in sufficient enzyme to prevent the effects of exogenous Glu by degrading it without affecting the response to endogenous transmitter) and; 3 - The Diltiazem experiment (i.e. using the calcium channel antagonist, diltiazem, to prevent the effect of exogenous Glu and yet not to interfere with endogenous transmitter release and action). The Tolerance and Diltiazem experiments produced results indicative of a clear dissociation between exogenous Glu and natural transmitter. The Glu decarboxylase experiment results were not so clear, producing both evidence for and against the hypothesis.     

When Public Health Becomes Politicized

Perhaps nothing symbolizes the current polarized political climate in the United States more than the world of public health. Public health schools and health departments are full of “true believers,” people willing to crusade for any program designed to reduce morbidity and mortality. But in the “real world,” proven programs and strategies—such as gun‐control measures, universal vaccination, and improved traffic safety—are routinely thwarted. Why do critics oppose efforts to improve the public's health? History can provide some answers.      

Application of the TIMI risk score for ST-elevation MI in the National Registry of Myocardial Infarction 3

CONTEXT: The Thrombolysis in Myocardial Infarction (TIMI) risk score for ST-elevation myocardial infarction (STEMI) is a simple integer score for bedside risk assessment of patients with STEMI. Developed and validated in multiple clinical trials of fibrinolysis, the risk score has not been validated in a community-based population. OBJECTIVE: To validate the TIMI risk score in a population of STEMI patients reflective of contemporary practice. DESIGN, SETTING, AND PARTICIPANTS: The risk score was evaluated among 84 029 patients with STEMI from the National Registry of Myocardial Infarction 3 (NRMI 3), which collected data on consecutive patients with myocardial infarction (MI) from 1529 US hospitals between April 1998 and June 2000. MAIN OUTCOME MEASURES: Ability of the TIMI risk score to correctly predict risk of death in terms of model discrimination (c statistic) and calibration (agreement of predicted and observed death rates). RESULTS: Patients in NRMI 3 tended to be older, to be more often female, and to have a history of coronary disease more often than those in the derivation set. Forty-eight percent received reperfusion therapy. The TIMI risk score revealed a significant graded increase in mortality with rising score (range, 1.1%-30.0%; P<.001 for trend). The risk score showed strong prognostic capacity overall (c = 0.74 vs 0.78 in derivation set) and among patients receiving acute reperfusion therapy (c = 0.79). Predictive behavior of the risk score was similar between fibrinolytic-treated patients (n = 23 960; c = 0.79) and primary percutaneous coronary intervention patients (n = 15 348; c = 0.80). In contrast, among patients not receiving reperfusion therapy, the risk score underestimated death rates and offered lower discriminatory capacity (c = 0.65). CONCLUSIONS: Sufficiently simple to be practical at the bedside and effective for risk assessment across a spectrum of patients, the TIMI risk score may be useful in triage and treatment of patients with STEMI who are treated with reperfusion therapy.     

The electrical stimulation of carbon nanotubes to provide a cardiomimetic cue to MSCs

Once damaged, cardiac muscle has little intrinsic repair capability due to the poor regeneration potential of remaining cardiomyocytes. One method of overcoming this issue is to deliver functional cells to the injured myocardium to promote repair. To address this limitation we sought to test the hypothesis that electroactive carbon nanotubes (CNT) could be employed to direct mesenchymal stem cell (MSC) differentiation towards a cardiomyocyte lineage. Using a two-pronged approach, MSCs exposed to medium containing CNT and MSCs seeded on CNT based polylactic acid scaffolds were electrically stimulated in an electrophysiological bioreactor. After electrical stimulation the cells reoriented perpendicular to the direction of the current and adopted an elongated morphology. Using qPCR, an upregulation in a range of cardiac markers was detected, the greatest of which was observed for cardiac myosin heavy chain (CMHC), where a 40-fold increase was observed for the electrically stimulated cells after 14 days, and a 12-fold increase was observed for the electrically stimulated cells seeded on the PLA scaffolds after 10 days. Differentiation towards a cardioprogenitor cell was more evident from the western blot analysis, where upregulation of Nkx2.5, GATA-4, cardiac troponin t (CTT) and connexin43 (C43) was seen to occur. This was echoed in immunofluorescent staining, where increased levels of CTT, CMHC and C43 protein expression were observed after electrical stimulation for both cells and cell-seeded scaffolds. More interestingly, there was evidence of increased cross talk between the cells as shown by the pattern of C43 staining after electrical stimulation. These results establish a paradigm for nanoscale biomimetic cues that can be readily translated to other electroactive tissue repair applications.