Structural plasticity of axon initial segment in spinal cord neurons underlies inflammatory pain.

ABSTRACT: Physiological or pathology-mediated changes in neuronal activity trigger structural plasticity of the action potential generation site-the axon initial segment (AIS). These changes affect intrinsic neuronal excitability, thus tuning neuronal and overall network output. Using behavioral, immunohistochemical, electrophysiological, and computational approaches, we characterized inflammation-related AIS plasticity in rat's superficial (lamina II) spinal cord dorsal horn (SDH) neurons and established how AIS plasticity regulates the activity of SDH neurons, thus contributing to pain hypersensitivity. We show that in naive conditions, AIS in SDH inhibitory neurons is located closer to the soma than in excitatory neurons. Shortly after inducing inflammation, when the inflammatory hyperalgesia is at its peak, AIS in inhibitory neurons is shifted distally away from the soma. The shift in AIS location is accompanied by the decrease in excitability of SDH inhibitory neurons. These AIS location and excitability changes are selective for inhibitory neurons and reversible. We show that AIS shift back close to the soma, and SDH inhibitory neurons' excitability increases to baseline levels following recovery from inflammatory hyperalgesia. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of inflammatory pain-mediated AIS plasticity in the central nervous system, which differentially affects the excitability of inhibitory SDH neurons and contributes to inflammatory hyperalgesia.

Prevalence of use of cardiovascular drugs in 499 patients with suspected coronary artery disease at time of hospitalization for coronary angiography and in 357 patients with obstructive coronary artery disease documented by coronary angiography.

In a prospective study of 499 patients with suspected coronary artery disease (CAD) hospitalized for coronary angiography, the prevalence of use of cardiovascular drugs at hospital admission was 80% for antiplatelet drugs, 66% for beta blockers, 55% for angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), 65% for lipid-lowering drugs, 24% for calcium channel blockers (CCBs), and 16% for nitrates. In 357 patients with obstructive CAD diagnosed by coronary angiography, the prevalence of use of these drugs at hospital discharge was 100% for antiplatelet drugs, 97% for beta blockers, 91% for ACE inhibitors or ARBs, 98% for lipid-lowering drugs, 17% for CCBs, and 27% for nitrates. Obstructive CAD was significantly more prevalent in men (P < 0.025), in cigarette smokers (P < 0.01), and in patients with hypertension, diabetes, or hypercholesterolemia (P < 0.001). Age, race, body mass index, and neck circumference were not significantly different for patients with versus without obstructive CAD.

Relation of moderate or severe reduction in glomerular filtration rate to number of coronary arteries narrowed >50% in patients undergoing coronary angiography for suspected coronary artery disease.

We investigated, in a prospective study of 1,007 patients who underwent coronary angiography for suspected coronary artery disease (CAD), the association of obstructive CAD with severe or moderate decrease in glomerular filtration rate (GFR) calculated from the Modification of Diet in Renal Disease equation. Baseline characteristics were similar in patients with a moderate or severe GFR decrease (<60 ml/min/1.73 m(2)) and those with a mild or no GFR decrease except for diabetes being present in 112 of 259 patients (43%) with a moderate or severe GFR decrease and in 206 of 748 patients (28%) with a mild or no GFR decrease (p <0.001). Three-vessel CAD was present in 138 of 259 patients (53%) with a moderate or severe GFR decrease and in 170 of 748 patients (23%) with a mild or no GFR decrease (p <0.001). One- to 3-vessel CAD was present in 225 of 259 patients (87%) with a moderate or severe GFR decrease and in 533 of 748 patients (71%) with a mild or no decrease in GFR (p <0.001). Logistic regression analysis showed that patients with a moderate or severe GFR decrease had a 4.1 times higher risk of developing 3-vessel CAD after controlling for the effect of diabetes compared with patients with a mild or no GFR decrease (relative risk 4.1, 95% confidence interval 3.0 to 5.5). In conclusion, a moderate or severe decrease in GFR is a significant risk factor for 1- to 3-vessel obstructive CAD, especially 3-vessel obstructive CAD.