Remodelling of gap junctions and connexin expression in diseased myocardium

Gap junctions form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the regular rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are expressed in the heart: connexin43 (Cx43), Cx40 and Cx45 are found in distinctive combinations and relative quantities in different, functionally-specialized subsets of cardiac myocyte. Mutations in genes that encode connexins have only rarely been identified as being a cause of human cardiac disease, but remodelling of connexin expression and gap junction organization are well documented in acquired adult heart disease, notably ischaemic heart disease and heart failure. Remodelling may take the form of alterations in (i) the distribution of gap junctions and (ii) the amount and type of connexins expressed. Heterogeneous reduction in Cx43 expression and disordering in gap junction distribution feature in human ventricular disease and correlate with electrophysiologically identified arrhythmic changes and contractile dysfunction in animal models. Disease-related alterations in Cx45 and Cx40 expression have also been reported, and some of the functional implications of these are beginning to emerge. Apart from ventricular disease, various features of gap junction organization and connexin expression have been implicated in the initiation and persistence of the most common form of atrial arrhythmia, atrial fibrillation, though the disparate findings in this area remain to be clarified. Other major tasks ahead focus on the Purkinje/working ventricular myocyte interface and its role in normal and abnormal impulse propagation, connexin-interacting proteins and their regulatory functions, and on defining the precise functional properties conferred by the distinctive connexin co-expression patterns of different myocyte types in health and disease.     

Evaluation of erythropoiesis in long-term hamster bone marrow suspension cultures: absence of a requirement for adherent monolayer cells

In long-term hamster bone marrow cultures, proliferation and differentiation of hemopoietic stem cells occurs for several months without need for hydrocortisone or adherent stromal elements, which are requirements for bone marrow growth in all other species studied. Only the most primitive erythroid progenitors (BFU-E) are produced in the cultures. Following treatment of the cells with erythropoietin, these progenitor cells undergo differentiation into mature hemoglobinized red blood cells. Concomitant addition of erythropoietin (Epo) and prostaglandin-E1 (PGE1) results in the production of large numbers of maturing red blood cells. In cultures stimulated with Epo and PGE1, as many as 70% of the cells are benzidine-positive, while Epo alone stimulated as many as 45% of the cells to become erythroid. Epo and PGE1 do not have any apparent deleterious effect on the continuous hemopoiesis occurring in these cultures. Under identical conditions, syngeneic adherent cell cultures do not produce any erythroid elements. The development of mature red blood cells from primitive erythroid precursors occurs in the presence of Epo alone and without any apparent need for adherent stromal elements. These cultures provide a useful in vitro model for dissecting the positive and negative signals that regulate erythropoiesis.     

Risk Stratification Among Survivors of Cardiac Arrest Considered for Coronary Angiography

BackgroundThe American College of Cardiology Interventional Council published consensus-based recommendations to help identify resuscitated cardiac arrest patients with unfavorable clinical features in whom invasive procedures are unlikely to improve survival.ObjectivesThis study sought to identify how many unfavorable features are required before prognosis is significantly worsened and which features are most impactful in predicting prognosis.MethodsUsing the INTCAR (International Cardiac Arrest Registry), the impact of each proposed “unfavorable feature” on survival to hospital discharge was individually analyzed. Logistic regression was performed to assess the association of such unfavorable features with poor outcomes.ResultsSeven unfavorable features (of 10 total) were captured in 2,508 patients successfully resuscitated after cardiac arrest (ongoing cardiopulmonary resuscitation and noncardiac etiology were exclusion criteria in our registry). Chronic kidney disease was used in lieu of end-stage renal disease. In total, 39% survived to hospital discharge. The odds ratio (OR) of survival to hospital discharge for each unfavorable feature was as follows: age >85 years OR: 0.30 (95% CI: 0.15 to 0.61), time-to-ROSC >30 min OR: 0.30 (95% CI: 0.23 to 0.39), nonshockable rhythm OR: 0.39 (95% CI: 0.29 to 0.54), no bystander cardiopulmonary resuscitation OR: 0.49 (95% CI: 0.38 to 0.64), lactate >7 mmol/l OR: 0.50 (95% CI: 0.40 to 0.63), unwitnessed arrest OR: 0.58 (95% CI: 0.44 to 0.78), pH <7.2 OR: 0.78 (95% CI: 0.63 to 0.98), and chronic kidney disease OR: 0.96 (95% CI: 0.70 to 1.33). The presence of any 3 or more unfavorable features predicted <40% survival. Presence of the 3 strongest risk factors (age >85 years, time-to-ROSC >30 min, and non-ventricular tachycardia/ventricular fibrillation) together or ≥6 unfavorable features predicted a ≤10% chance of survival to discharge.ConclusionsPatients successfully resuscitated from cardiac arrest with 6 or more unfavorable features have a poor long-term prognosis. Delaying or even forgoing invasive procedures in such patients is reasonable.     

Regional brain activation during proximal stomach distention in humans: A positron emission tomography study

BACKGROUND & AIMS: Hypersensitivity to proximal gastric distention due to abnormal central nervous system processing of visceral stimuli has been suggested as a possible underlying pathophysiologic mechanism in functional dyspepsia. However, the cortical regions activated by distention of the proximal stomach have not been identified. The aim of this study was to investigate regional brain activation during painful and nonpainful proximal gastric distention in humans. METHODS: Positron emission tomography of the brain was performed in 11 healthy volunteers during 4 conditions: (1) no distention and isobaric distention to the individual thresholds for (2) first, (3) marked, and (4) unpleasant sensation. Data were analyzed using statistical parametric mapping. RESULTS: During maximal distention relative to baseline, significant (P corrected <.05) regional brain activation occurred in the left and right gyrus postcentralis (Brodmann area [BA] 43), the left gyrus temporalis superior (BA 38), the right gyrus frontalis inferior (BA 47, orbitofrontal cortex), the right midanterior cingulate gyrus (BA 24), the right anterior insula, and the left cerebellar hemisphere. These areas showed a progressive increase in activation with increasing intensity of the distending stimulus. CONCLUSIONS: We found evidence for a neuronal network processing distention stimuli of the proximal stomach that is overall consistent with the "visceral stimulation network" described in the literature. In addition, we found activation of the orbitofrontal cortex, confirming its role as a convergence zone for processing of food-related stimuli and regulation of hunger, appetite, satiety, and food intake. We found no evidence for a functional neuroanatomic divergence in the processing of noxious and innocuous gastric stimuli.