Two types of muscarinic response to acetylcholine in mammalian cortical neurons.

Applications of acetylcholine (AcCho) to pyramidal cells of guinea pig cingulate cortical slices maintained in vitro result in a short latency inhibition, followed by a prolonged increase in excitability. Cholinergic inhibition is mediated through the rapid excitation of interneurons that utilize the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This rapid excitation of interneurons is associated with a membrane depolarization and a decrease in neuronal input resistance. In contrast, AcCho-induced excitation of pyramidal cells is due to a direct action that produces a voltage-dependent increase in input resistance. In the experiments reported here, we investigated the possibility that these two responses are mediated by different subclasses of cholinergic receptors. The inhibitory and slow excitatory responses of pyramidal neurons were blocked by muscarinic but not by nicotinic antagonists. Pirenzepine was more effective in blocking the AcCho-induced slow depolarization than in blocking the hyperpolarization of pyramidal neurons. The two responses also varied in their sensitivity to various cholinergic agonists, making it possible to selectively activate either. These data suggest that AcCho may produce two physiologically and pharmacologically distinct muscarinic responses on neocortical neurons: slowly developing voltage-dependent depolarizations associated with an increase in input resistance in pyramidal cells and short-latency depolarizations associated with a decrease in input resistance in presumed GABAergic interneurons.     

Circulating CD4‐positive lymphocyte levels as predictor of response to induction chemotherapy in patients with advanced laryngeal cancer

Background. Tumor regression after induction chemotherapy (ICT) identifies laryngeal cancers that are responsive to chemoradiation. Patient immune parameters have recently been associated with response to chemotherapy and may identify responding patients. A retrospective analysis was performed to determine if pretreatment, circulating T lymphocyte levels predicted ICT response in patients with advanced laryngeal cancer. Methods. Pretreatment, circulating T lymphocyte subpopulations were correlated with response to therapy and survival. Results were compared with similar data from an identical phase II trial involving patients with oropharyngeal cancer. Results. An increased percentage of CD4+ cells predicted response to ICT and suggested improved survival in patients with laryngeal, but not oropharyngeal, cancer. In the combined group of patients, increased CD4 levels predicted response to ICT. Conclusion. These findings demonstrate the potential importance of the immune system in chemotherapy response and clinical outcome. Differences in findings between patients with advanced laryngeal and oropharyngeal cancer may reflect different cellular immunity function in the patients with human papillomavirus (HPV)‐16+ oropharyngeal cancer. © 2013 Wiley Periodicals, Inc. Head Neck 36 : 9–14, 2014     

Cor Pulmonale Parvus in Chronic Obstructive Pulmonary Disease and Emphysema : The MESA COPD Study

Background

The classic cardiovascular complication of chronic obstructive pulmonary disease (COPD) is cor pulmonale or right ventricular (RV) enlargement. Most studies of cor pulmonale were conducted decades ago.

Objectives

This study sought to examine RV changes in contemporary COPD and emphysema using cardiac magnetic resonance (CMR) imaging.

Methods

We performed a case-control study nested predominantly in 2 general population studies of 310 participants with COPD and control subjects 50 to 79 years of age with ≥10 pack-years of smoking who were free of clinical cardiovascular disease. RV volumes and mass were assessed using magnetic resonance imaging. COPD and COPD severity were defined according to standard spirometric criteria. The percentage of emphysema was defined as the percentage of lung regions <−950 Hounsfield units on full-lung computed tomography; emphysema subtypes were scored by radiologists. Results were adjusted for age, race/ethnicity, sex, height, weight, smoking status, pack-years, systemic hypertension, and sleep apnea.

Results

Right ventricular end-diastolic volume (RVEDV) was reduced in COPD compared with control subjects (−7.8 ml; 95% confidence interval: −15.0 to −0.5 ml; p = 0.04). Increasing severity of COPD was associated with lower RVEDV (p = 0.004) and lower RV stroke volume (p < 0.001). RV mass and ejection fraction were similar between the groups. A greater percentage of emphysema also was associated with lower RVEDV (p = 0.005) and stroke volume (p < 0.001), as was the presence of centrilobular and paraseptal emphysema.

Conclusions

RV volumes are lower without significant alterations in RV mass and ejection fraction in contemporary COPD, and this reduction is related to the greater percentage of emphysema on computed tomography.     

The Relationship of Left Ventricular Trabeculation to Ventricular Function and Structure Over a 9.5-Year Follow-Up : The MESA Study

Background

Left ventricular (LV) trabeculation is highly variable among individuals and is increased in some diseases (e.g., congenital heart disease or cardiomyopathies), but its significance in population-representative individuals is unknown.

Objectives

The goal of this study was to determine if excessive LV trabeculation in population-representative individuals is associated with preceding changes in cardiac volumes and function.

Methods

For technical reasons, the extent of trabeculation, which is expressed as the ratio of noncompacted to compacted (NC/C) myocardium, was measured on cardiac magnetic resonance (CMR) long-axis cine images in 2,742 participants in the MESA (Multi-Ethnic Study of Atherosclerosis) (mean age 68.7 years; 52.3% women; 56.4% with hypertension; 16.8% with diabetes) at examination 5. These were considered in quintiles of trabeculation extent; the NC/C ratio of quintile 5 was 2.46 to 5.41. We determined the relationship between the maximal NC/C ratio and the preceding change (9.5 years between examinations 1 and 5) in end-systolic volume indexed (ESVi) to body surface area. Secondary analyses assessed the associations between the maximal NC/C ratio and preceding changes in end-diastolic volume indexed (EDVi) to body surface area and the ejection fraction (EF).

Results

Over 9.5 years, the ESVi decreased by 1.3 ml/m², the EDVi decreased by 5.1 ml/m², and the EF decreased by 0.6% (p < 0.0001). Even in subjects with excessive trabeculation, there were no clinically relevant differences in LV volumes and systolic function changes among the quintiles of trabeculation extent.

Conclusions

Greater extent of, and even excessive, LV trabeculation measured in end-diastole in asymptomatic population-representative individuals appeared benign and was not associated with deterioration in LV volumes or function during an almost 10-year period.     

Functional disability and death wishes in older Europeans: results from the EURODEP concerted action

Purpose

Physical illness has been shown to be a risk factor for suicidal behaviour in older adults. The association between functional disability and suicidal behaviour in older adults is less clear. The aim of this study was to examine the relationship between functional disability and death wishes in late life.

Methods

Data from 11 population studies on depression in persons aged 65 and above were pooled, yielding a total of 15,890 respondents. Level of functional disability was trichotomised (no, intermediate, high). A person was considered to have death wishes if the death wish/suicidal ideation item of the EURO-D scale was endorsed. Odds ratios for death wishes associated with functional disability were calculated in a multilevel logistic regression model.

Results

In total, 5 % of the men and 7 % of the women reported death wishes. Both intermediate (OR 1.89, 95 % CI 1.42; 2.52) and high functional disability (OR 3.22, 95 % CI 2.34; 4.42) were associated with death wishes. No sex differences could be shown. Results remained after adding depressive symptoms to the model.

Conclusions

Functional disability was independently associated with death wishes in older adults. Results can help inform clinicians who care for older persons with functional impairment.