Dissimilar Action of Two Cyclic Adenosine-Monophosphate Analogues on the Sodium Current in Intact Rat Papillary Muscle

In intact papillary muscles from rat we have found with the loose-patch-clamp technique an increase of the fast cardiac sodium current (I_Na⁺) by isoproterenol (ISO). In this study we have tested two membrane permeable analogues of the intracellular second messenger cyclic adenosine-monophosphate (cAMP) to investigate the intracellular pathway: 8-Br-cAMP (50 μM) and the newer developed S_p5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole-3′, 5′-cyclic-monophosphor-othioate (5,6-DCl-cBiMPS, 20 μM). The availability of I_Na⁺ was determined with test pulses to ± 0 mV every 3.5 seconds after 2.5-second conditioning between -130 mV and-50 mV and a holding potential at the resting potential of the cell under examination, and after wash-in of either compound. The peak currents were fit to a Boltzmann equation, and expressed by the maximal attainable current INa⁺_Na,max the mid-point potential V½, and a steepness parameter a. Values are given by mean ± SEM. 8-Br-cAMP showed a significant shift of the availability curve in the hyperpolarized direction (V½= -82 ± 2 mV vs - 66 ± 2 mV, n = 5, P < 0.05) with only minor changes of I⁺_No,max and a. In contrast, 5,6-DCI-cBiMPS had no significant effect on V½ but increased I⁺_Na,max by 8%± 2% versus control (n = 5. P < 0.05). In an intact muscle preparation we have found that 5,6-DCI-cBiMPS has a similar effect as that observed with the β-adrenergic agonist ISO (100 nM), whereas 8-Br-cAMP exhibited a dissimilar action. This indicates, that ihe effects of ISO are transmitted by the cAMP system. On the other hand, 8-Br-cAMP, which is not as permeable and specific an activator of the cAMP dependent proteinkinase, may have other effects on the sodium channel, perhaps mediated through purinergic receptors.     

Transient impairment of peripheral blood lymphocyte function during PUVA therapy

Three parameters of immune function--enumeration of circulating T and B lymphocytes and response of lymphocytes to graduated doses of phytohaemagglutinin (PHA)--were examined serially in eleven patients with psoriasis before, during, and after an intensive course of PUVA therapy. A trend was detected for the lymphocyte response to PHA to fall during the first week of treatment and then rise back towards the pre-treatment level. No alteration was found in the percentage or absolute numbers of circulating T and B lymphocytes. This study shows that routine PUVA therapy can induce an alteration in immune function but that this alteration is slight and short-lived.     

Right Atrial Remodeling is More Advanced in Patients with Atrial Flutter Than with Atrial Fibrillation

Atrial Remodeling in Atrial Flutter. Introduction: Atrial fibrillation (AF) and atrial flutter (AFL) are related arrhythmias with common triggers, yet in individual patients either AF or AFL often predominates. We performed detailed electrophysiologic (EP) and electroanatomic (EA) studies of the right atrium (RA) in patients with AF and AFL to determine substrate differences that may explain the preferential expression of AF/AFL in individual patients. Methods: Patients with AF (n = 13) were compared to patients with persistent AFL (n = 10). Detailed studies were performed, and 3‐dimensional electroanatomic mapping studies were created and the RA was divided into 4 segments for regional analysis. Global, septal, lateral, anterior, and posterior segments were compared for analysis of: bipolar voltage; proportion of low‐voltage areas and areas of electrical silence; conduction times; and proportion of abnormal signals (fractionated signals and double potentials). Results: Compared to patients with AF, patients with AFL had (1) lower bipolar voltage and an increase in the proportion of low‐voltage areas; (2) an increase in the proportion of complex signals; and (3) prolongation of activation times. Conclusions: Patients with AFL showed more advanced remodeling than patients with AF with slowed conduction, lower voltage areas with regions of electrical silence, and a greater proportion of complex signals, particularly in the posterior RA. These changes facilitate the stabilization of AFL and may explain why some patients are more likely to develop AFL as a sustained clinical arrhythmia. (J Cardiovasc Electrophysiol, Vol. 23 pp. 1067‐1072, October 2012)     

Changes in sleepiness and body temperature precede nocturnal sleep onset: Evidence from a polysomnographic study in young men

Recent research has shown a close temporal relationship between the nocturnal decrease in rectal core temperature and the initiation of sleep. However, there is not yet a clear temporal relationship between changes in peripheral and core temperatures and nocturnal sleep onset. We recorded body temperatures in 14 adult males (age±SEM=22.1±0.6 y), who attended the sleep laboratory for an adaptation night and two counterbalanced experimental sessions. Subjects self-selected lights-out on one experimental night (the Habitual Sleep condition). To determine the relationship between body temperature changes and sleep onset, lights out was delayed until after 01.00 hours on the other experimental night (Delayed Sleep condition). Individual datasets in both conditions were expressed relative to the time of sleep onset in the Habitual Sleep condition only, so that they were aligned at identical clock times. Saliva samples confirmed that mean dim light melatonin onset (DLMO) occurred at 00.10±00.16 hours in the Delayed Sleep condition, which was after habitual sleep onset at 23.44±00.08 hours. Rectal core temperature (Tc) decreased significantly over time only in the Habitual Sleep condition ( P < 0.01). For the 20 min before habitual sleep onset, Delayed Sleep Tc was on average 0.1°C higher than Tc in the Habitual Sleep condition ( P < 0.01). The greater decline in Habitual Sleep Tc was associated with significantly increased peripheral hand and foot skin temperatures before sleep (both P < 0.05). Subjective sleepiness measures were higher in the Habitual Sleep onset condition from 150 min prior until sleep onset ( P < 0.01). From these results it is reasonable to infer that a sequence of thermoregulatory and sleep propensity changes occur before, but are associated with habitual sleep onset, as the changes are significantly attenuated if sleep is delayed.     

Cardiac Stimulation Threshold in Familial Amyloidosis with Polyneuropathy

It has been suggested that a higher cardiac stimulation threshold reduces the applicabilty of pacemaker therapy in cardiac amyloidosis. We therefore reviewed threshold data in patients with familial amyloidosis with polyneuropathy (FAP), which is an inherited type of systemic amyloidosis, invariably involving the heart. Fourteen FAP patients treated with a pacemaker were studied. The mean (±SD) voltage stimulation threshold during implantation was 1.0 ± 0.5 V, and noninvasive follow-up 6 months later revealed a mean Vario threshold of 1.9 ± 0.5 V. Beyond this time, the threshold tended to be stable, and high threshold exit block did not occur in any patient. Several FAP patients did show a moderately elevated threshold, and a multiprogrammable pulse generator with a high output capability is recommended when pacemaker therapy is considered in these patients.     

Light-induced Apoptosis: Differential Timing in the Retina and Pigment Epithelium

Apoptosis is a genetically regulated form of cell death. Individual cells show condensed nuclear chromatin and cytoplasm, and biochemical analysis reveals fragmentation of the DNA. Ensuing cellular components, apoptotic bodies, are removed by macrophages or neighboring cells. Genes involved in the regulation of apoptosis as well as stimuli and signal transduction systems, are only beginning to be understood in the retina. Therefore, we developed a new in vivo model system for the investigation of events leading to apoptosis in the retina and the pigment epithelium. We induced apoptosis in retinal photoreceptors and the pigment epithelium of albino rats by exposure to 3000 lux of diffuse, cool white fluorescent light for short time periods of up to 120 minutes. Animals were killed at different time intervals during and after light exposure. The eyes were enucleated and the lower central retina was processed for light- and electron microscopy. DNA fragmentation was analysed in situ by TdT-mediated dUTP nick-end labeling (TUNEL) or by gel electrophoresis of total retinal DNA. We observed that the timing of apoptosis in the photoreceptors and pigment epithelium was remarkably different, the pigment epithelium showing a distinct delay of several hours before the onset of apoptosis. In photoreceptors, apoptosis was induced within 90 minutes of light exposure, with the morphological appearance of apoptosis preceding the fragmentation of DNA. In the pigment epithelium, the morphological appearance of apoptosis and DNA fragmentation were coincident. Different regulative mechanisms may lead to apoptotic cell death in the retinal photoreceptors and pigment epithelium. This in vivo model system will allow measurement of dose-responses, a potential spectral dependence and the molecular background of apoptotic mechanisms in the retina.