Orthodeoxia-platypnea due to intracardiac shunting relief with transcatheter double umbrella closure

The safety and efficacy of transcatheter clamshell occlusion of patent foramen ovale for relief of severe arterial desaturation and dyspnea in the upright position due to intracardiac shunting were examined in eight patients with excessive risk of surgical patent foramen ovale closure. All patients had successful reduction of intracardiac shunting with an immediate rise in oxygen saturation ?95% by implantation of a clamshell device on the atrial septum. Despite two early incidents of device embolization, retrieval and immediate re-implantation, and one patient with nonsustained atrial and ventricular arrhythmias, there were no adverse clinical sequelae. In follow-up evaluation transcatheter clamshell closure of patent foramen ovale has provided persistent relief from shuntrelated arterial desaturation and symptomatology in all living patients. © 1995 Wiley-Liss, Inc.     

Prolactin-releasing peptide and its homolog RFRP-1 act in hypothalamus but not in anterior pituitary gland to stimulate stress hormone secretion

The RF-amide peptides (RFRPs), including prolactin (PRL)-releasing peptide-31 (PrRP-31) and RFRP-1, have been reported to stimulate stress hormone secretion by either direct pituitary or indirect hypothalamic actions. We examined the possible direct effects of these peptides on PRL and adrenocorticotropin (adrenocorticotropic hormone [ACTH]) release from dispersed anterior pituitary cells in culture and on PRL and ACTH secretion following intracerebroventricular (icv) administration in vivo. Neither peptide significantly altered PRL or ACTH release from cultured pituitary cells (male rat donors). Central administration of 1.0 and 3.0 nmol of PrRP-31, but only the higher dose of RFRP-1, significantly elevated serum corticosterone levels in conscious male rats. The effect of PrRP-31 was not blocked by pretreatment (iv) with the corticotropin-releasing hormone (CRH) antagonist, α-helical CRH 9–41; however, pretreatment of the animals (iv) with an antiserum to CRH significantly lowered the hypothalamic-pituitary-adrenal axis response to central administration of PrRP-31. On the other hand, the release of PRL was significantly elevated by 3.0 nmol of RFRP-1, but not PrRP-31, in similarly treated, conscious male rats. Pretreatment with the catecholamine synthesis inhibitor, α-methyl-para-tyrosine, prevented the stimulation of PRL secretion observed following central administration of RFRP-1. RFRP-1 similarly did not alter PRL secretion in rats pretreated with the dopamine, D₂ receptor blocker, domperidone. These results suggest that the RF-amide peptides are not true neuroendocrine regulators of stress hormone secretion in the rat but, instead, act centrally to alter the release of neuroendocrine factors that do act in the pituitary gland to control PRL and ACTH release. In the case of RFRP-1, stimulation of PRL secretion is potentially owing to an action of the peptide to inhibit dopamine release into the median eminence. The corticosterone secretion observed following central administration of PrRP-31 does not appear, based on our current results, to be solely owing to an action of the peptide on CRH-producing neurons but, instead, may be a result of the ability of PrRP-31 to increase as well the exposure of the corticotrophs in vivo to other ACTH secretagogues, such as oxytocin or vasopressin.     

Cell distributions and functions of Toll-like receptor 4 studied by fluorescent gene constructs

Bacterial lipopolysaccharide (LPS) is recognized in mammals by a receptor complex composed of CD14, Toll-like receptor 4 (TLR4), and MD-2. The detailed mechanisms of how TLR4 transmits the signal from the outside to the inside of the cell remain to be elucidated. One way of studying TLR4 signaling mechanisms is to construct chimeras of TLR molecules C-terminally fused to fluorescent proteins and stably express these constructs in cells. Such constructs are functional when transfected into HEK293 epithelial cells. Confocal microscopy of TLR4 expression in live cells demonstrated pronounced expression on the plasma membrane as well in the Golgi apparatus. Studies were performed to clarify whether expression of TLR4 in the Golgi was necessary for LPS stimulation. Rapid recycling of TLR4/CD14/MD-2 complexes between the Golgi and the plasma membrane was a prominent phenomenon. In agreement with other types of plasma membrane receptors, aggregation of TLR4 by immobilized TLR4 antibodies was sufficient to induce signaling. Also, pharmacological disruption of the Golgi did not inhibit LPS induced NF-kappaB activation. Furthermore, LPS stimulation recruited the adapter molecule, MyD88, to the inside of the plasma membrane. Thus, LPS signaling commences on the plasma membrane and is independent of trafficking to the Golgi.     

Temporal integration of melatonin infusion duration: signal averaging versus frequency dependence

Day length affects somatic and reproductive physiology of Siberian hamsters via regulation of the duration of nocturnal pineal melatonin secretion. Nightly 'long' (e.g. 12 hr) or 'short' (e.g. 6 hr) melatonin signals inhibit or stimulate gonadal growth, respectively. When long and short signals are presented in combination, however, neuroendocrine mechanisms exhibit a frequency-dependent response, stimulating gonadal growth only if short signals are presented every second night or more frequently. The present experiments further assessed formal models for the temporal integration of melatonin signals changing abruptly in duration from night to night. Photo-inhibited Siberian hamsters were housed in constant light and infused subcutaneously with various combinations of nightly short or long melatonin signals according to one of the several regimes that varied the frequency of short melatonin signal occurrence, average duration of the nightly melatonin signal, or both. Six weeks of nightly alternating short and long signals yielded different gonadal responses depending on the average melatonin signal duration. Moreover, when average melatonin signal duration was held constant between groups, gonadal stimulation was independent of the frequency of the constituent melatonin signals except when the duration of the short signal was reduced to 3 hr. Thus, neuroendocrine mechanisms do not solely categorize melatonin signals as either long or short but attend also to the duration of each component signal. In the majority (six of seven) of infusion regimes, reproductive responses to chimeric patterns of long and short melatonin signals were compatible with a simple signal-averaging mechanism.