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El valor de los parámetros del electrocardiograma (ECG) de repolarización asociados al riesgo de arritmias ventriculares (AVs) en el síndrome de tako-tsuboes controvertido. Nuestro objetivo fue identificar predictores ECG de AVs subagudas, definidas como aquellas ocurridas después de las primeras 48 horas desde el ingreso.

This article focuses on debates on philosophical knowledge, mathematics, and the empirical sciences by analyzing the positions on cosmological and astronomical knowledge, around 1800, of three German authors: Herder, Schelling, and Hegel. I show the mutual interdependence of Schelling’s and Hegel’s Naturphilosophieand Herder’s Ideen, and I then demonstrate that the latter’s position during the last years of his life was a reaction to Schelling’s and Hegel’s speculative philosophy. While Herder seems to ignore the works of the Naturphilosophenin his journal Adrastea, in fact he participated in a very lively debate that included Schelling’s Weltseeleand Hegel’s Dissertatio de Orbitis Planetarum.

Microplastics (MPs) are ubiquitous contaminants of the marine environment, and the deep seafloor is their ultimate sink compartment. Manipulative and field experiments provided evidence of the ingestion of MPs by deep-sea fauna, but knowledge of MPs’ fate once ingested still remains scant. We provide evidence of MP partial retention and fragmentation mediated by digestion activity of a Norwegian langoustine, a good bioindicator for MP contamination of the deep sea. We report here that MPs in the intestines were more abundant and significantly smaller (up to 1 order of magnitude in surface) than those in the stomachs. Our results show that the stomach can act as a size-bottleneck for ingested MPs, enhancing the retention of larger particles within the stomach and promoting fragmentation into smaller plastic debris, which is then released in the intestine. Our results provide evidence that the langoustine is responsible for the fragmentation of MPs already accumulated in sediments through its scavenging activity and digestion. These findings highlight the existence of a new peculiar kind of “secondary” MPs, introduced in the environment by biological activities, which could represent a significant pathway of plastic degradation in a secluded and stable environment such as the deep sea.

Cardiac amyloidosis is an infiltrative myocardial disease whose prevalence significantly increased in recent years. Its clinical history is changing due to the advent of novel therapies, and careful risk stratification has become impelling. Arrhythmias, frequently found during the course of the disease, include conduction system disease, atrial fibrillation (AF), and ventricular arrhythmias (VAs). Arrhythmic risk stratification is a key to identify those patients at higher risk to develop advanced atrioventricular blocks, asymptomatic AFs, or major VAs. This carries significant clinical implications concerning the indication and timing of implantable cardiac devices, as well as the initiation of anticoagulation therapy.

Sinus bradycardia might be a severe clinical problem, if symptomatic pacemaker implantation is needed. In younger patients this will lead to several battery changes, higher infectious risk and psychological issues. When sinus bradycardia seems related to vagal hypertone, intracavitary ablation of atrial ganglionated plexus has recently been proposed as an alternative to pacemaker implantation in symptomatic younger patients. A 44–year–old patient was admitted to the emergency department for lipothymia and fatigue. The ECG showed marked sinus bradycardia with a heart rate of 35 bpm and continuous ECG monitoring revealed episodes of Mobitz I second degree AV block and 2:1 AV block. The transthoracic echocardiography was normal. In order to reduce the effect of vagal hypertone on the heart, catheter ablation of parasympathetic atrial ganglionated plexus was performed. In the right atrium the electrophysiological study showed fragmented potentials near caval vein openings and coronary sinus osthium, while in the left atrium these were found in the posterior wall close to the pulmonary veins and near the left part of coronary sinus. Catheter stimulation of these zones determined asystolic pauses and induction of atrial fibrillation with spontaneous resolution. Catheter radio–frequency ablation was performed, at the end of the procedure increase of heart rate at 70 bpm was observed and atrial fibrillation was no more inducible during pacing. Atrioventricular Wenckebach point recorded before the procedure was 730 ms and it passed to 430 ms. At continuous ECG monitoring the heart rate remained higher than 65 bpm all over the hospitalization, without any other meaningful arrhythmias. Ablation of parasympathetic atrial ganglionated plexus is still an experimental technique but it is proving to be very interesting and promising. In the case we described the patient took a real advantage from the procedure that was measurable both with the improve of heart rate and reduction of Wenckebach point. During the procedure we associated the site of fragmented potentials with the position of each plexus; stimulation of these sites evocated a strong vagal response, confirming that fragmented potentials can be used to localize the plexus. Some authors affirmed that ablation only on right atrium might be sufficient; however, we preferred to ablate in both atria in order to make the procedure more effective. More studies are needed to identify the correct site.

Hyperthyroidism can strongly impact cardiac function. Thyrotoxicosis enhances myocardiocytes metabolism and it can be responsible for hyperdynamic circulation state leading to heart failure with preserved ejection fraction, but also left ventricle dilatation and severe contractile function impairment. It can furthermore provoke arrhythmias, mostly atrial fibrillation, but, as we are going to discuss in this case, even ventricular arrhythmias. A 40–year–old woman came to our emergency department for chest pain. ECG showed reduced R waves voltage in precordial leads and troponin I values were normal. The echocardiogram showed severe left ventricle disfunction with global hypokinesia (EF 35%) and enlarged left ventricle (LVEDD 65 mm). Blood tests revealed severe hyperthyroidism with extremely low level of TSH, FT3 13,45 pg/ml, FT4 3,4 ng/ml and thyroid echography documented multiple solid nodular formations with hypo–isoechogenic signal. She underwent a coronary angiography that showed patent coronary arteries, and a cardiac magnetic resonance confirming severe contractile impairment and hypertrabeculation of the apex and lateral wall. On the assumption of a dilated cardiomyopathy secondary to hyperthyroidism, we started treatment with methimazole, ACE inhibitors and propranolol. During hospitalization, continuous ECG monitoring recorded several episodes of non–sustained ventricular tachycardia, the longest lasting 22 seconds, so the patient was discharged with a wearable cardioverter–defibrillator. It did not record any arrhythmias and it was dismissed a month later. After almost two months of therapy, the echocardiogram showed mild left ventricular contractility improvement (EF 45%), and blood tests documented partial reduction of hyperthyroidism. A 24–hour ECG Holter did not record any arrhythmias and the patient remained asymptomatic during all the period after discharge. Even if rare, scientific literature confirms that dilated cardiomyopathy with reduced ejection fraction can occur as a complication of hyperthyroidism. After the exclusion of an ischemic cause, we underline the need for adequate initiation of treatments for thyrotoxicosis and heart failure, in order to improve chance of left ventricular function recovery. In the case discussed, after two months of therapy, EF was still not completely restored but improved from 35% to 45%, and concurrently arrhythmic risk did clearly decrease.

Atrial thrombosis is an uncommon complication of cardiac transplant, especially when performed with standard technique. Pathogenetic mechanisms might involve atrial anatomy distortion and abnormalities in its contractile function, which induce flow stasis and thrombus formation, mostly on the surgical suture. A 77–year–old man underwent orthotopic heart transplantation in 2000 for post–ischemic dilated cardiomyopathy. In 2019 he was diagnosed with diffuse large B–cell lymphoma treated with chemotherapy. On March 2021, during follow up period, he had a total body CT scan which showed a submandibular space–occupying lesion, likely as a disease recurrence, and a large atrial mass (30x50 mm). For this reason, he was admitted to the emergency department. Echocardiography documented a massive hyperechogenic formation in an enlarged left atrium. In order to rule out a neoplastic nature, a cardiac CMR was performed, confirming the presence of an oval mass adhering to the posterior left atrial wall with partial involvement of pulmonary veins ostia, with inhomogeneous isointense signal on T1–weighted sequences and hyper–isointense signal on T2–weighted sequences, without significant contrast enhancement, likely representing an endoluminal thrombotic formation. Given the patient’s clinical status and his hemodynamic stability, a surgical excision was deferred. The patient was discharged on oral anticoagulant therapy with Warfarin (INR target 2–3). Three months later, a chest CT showed a meaningful mass reduction (11x18mm), which was no longer visible at echocardiography. About 9 months later, complete disappearance of the atrial mass was found at a CT scan. According to scientific literature, differential diagnosis of a newly discovered atrial mass in a transplanted heart includes thrombosis or neoplasia. Thrombosis occurs usually early after surgery, but due to promoting factors, it can arise after many years. The most likely triggering condition is an acquired prothrombotic status: in our case the likely lymphoma recurrence may have led to thrombogenesis. In order to exclude with confidence cardiac metastasis, histological examination would have been necessary. Nevertheless, the meaningful mass reduction, as early as three months after starting oral anticoagulation, and its disappearance nine months after, strongly suggests for atrial thrombosis.

Both benzodiazepines and γ-hydroxybutyric acid (GHB) are used to treat alcohol withdrawal syndrome. The molecular basis for this therapeutic efficacy was investigated with primary cultures of rat cerebellar granule cells. Long-term exposure of these cells to ethanol (100 mM, 5 days) reduced the abundance of mRNAs encoding the γ2L and γ2S subunits of the GABA type A receptor (−32 and −23%, respectively) but failed to affect that of α1, α4, or α6subunit mRNAs. Subsequent ethanol withdrawal resulted in decreases in the amounts of α1(−29%), α6(−27%), γ2L (−64%), and γ2S (−76%),subunit mRNAs that were maximal after 6 to 12 h. In contrast, 3 h after ethanol withdrawal, the abundance of the α4subunit mRNA was increased by 46%. Ethanol withdrawal did not affect neuronal morphology but reduced cellular metabolic activity. The increase in α4subunit was confirmed by functional studies showing a positive action of flumazenil in patch clamp recordings of GABA-stimulated currents after ethanol withdrawal. Diazepam (10 μM) or GHB (100 mM) prevented the increase in the amount of the α4subunit mRNA, the metabolic impairment, and the positive action of flumazenil induced by ethanol withdrawal but failed to restore the expression of the α1and γ2subunits. The antagonism by GHB seems not to be mediated by a direct action at GABAAR because GHB failed to potentiate the effects of GABA or diazepam on Cl−currents mediated by GABA type A receptor.

Both benzodiazepines and gamma-hydroxybutyric acid (GHB) are used to treat alcohol withdrawal syndrome. The molecular basis for this therapeutic efficacy was investigated with primary cultures of rat cerebellar granule cells. Long-term exposure of these cells to ethanol (100 mM, 5 days) reduced the abundance of mRNAs encoding the gamma(2)L and gamma(2)S subunits of the GABA type A receptor (-32 and -23%, respectively) but failed to affect that of alpha(1), alpha(4), or alpha(6) subunit mRNAs. Subsequent ethanol withdrawal resulted in decreases in the amounts of alpha(1) (-29%), alpha(6) (-27%), gamma(2)L (-64%), and gamma(2)S (-76%),subunit mRNAs that were maximal after 6 to 12 h. In contrast, 3 h after ethanol withdrawal, the abundance of the alpha(4) subunit mRNA was increased by 46%. Ethanol withdrawal did not affect neuronal morphology but reduced cellular metabolic activity. The increase in alpha(4) subunit was confirmed by functional studies showing a positive action of flumazenil in patch clamp recordings of GABA-stimulated currents after ethanol withdrawal. Diazepam (10 microM) or GHB (100 mM) prevented the increase in the amount of the alpha(4) subunit mRNA, the metabolic impairment, and the positive action of flumazenil induced by ethanol withdrawal but failed to restore the expression of the alpha(1) and gamma(2) subunits. The antagonism by GHB seems not to be mediated by a direct action at GABA(A)R because GHB failed to potentiate the effects of GABA or diazepam on Cl(-) currents mediated by GABA type A receptor.

The effects of ganaxolone, a synthetic analog of the endogenous neuroactive steroid allopregnanolone, on the function and expression of GABA(A) receptors were determined. Electrophysiological recordings demonstrated that ganaxolone potentiated with a potency and efficacy similar to those of allopregnanolone the Cl- currents evoked by GABA at recombinant human GABA(A) receptors (comprising alpha1beta2gamma2L or alpha2beta2gamma2L subunit assemblies) expressed in Xenopus oocytes. Exposure of cultured rat cerebellar granule cells to 1 microM ganaxolone for 5 days had no effect on the abundance of mRNAs encoding the alpha1, alpha2, alpha3, alpha4, alpha5, gamma2L, or gamma2S subunits of the GABA(A) receptor. Withdrawal of ganaxolone after such long-term treatment, however, induced an increase in the abundance of alpha2, alpha4, and alpha5 subunit mRNAs and a decrease in the amounts of alpha1, gamma2L, and gamma2S subunit mRNAs. These changes were maximal 3 to 6 h after drug withdrawal and were reversible, being no longer apparent after 24 h. These results suggest that long-term exposure of cerebellar granule cells to ganaxolone does not affect the sensitivity of the GABA(A) receptor to several positive modulators. Nevertheless, the reduction in the amounts of the alpha1 and gamma2 subunit mRNAs together with the increase in the abundance of the alpha4 subunit mRNA induced by abrupt discontinuation of long-term treatment with ganaxolone suggest that withdrawal of this drug might result in a reduced response to classic benzodiazepines.

The effects of ganaxolone, a synthetic analog of the endogenous neuroactive steroid allopregnanolone, on the function and expression of GABAAreceptors were determined. Electrophysiological recordings demonstrated that ganaxolone potentiated with a potency and efficacy similar to those of allopregnanolone the Cl−currents evoked by GABA at recombinant human GABAAreceptors (comprising α1β2γ2L or α2β2γ2L subunit assemblies) expressed in Xenopusoocytes. Exposure of cultured rat cerebellar granule cells to 1 μM ganaxolone for 5 days had no effect on the abundance of mRNAs encoding the α1, α2, α3, α4, α5, γ2L, or γ2S subunits of the GABAAreceptor. Withdrawal of ganaxolone after such long-term treatment, however, induced an increase in the abundance of α2, α4, and α5 subunit mRNAs and a decrease in the amounts of α1, γ2L, and γ2S subunit mRNAs. These changes were maximal 3 to 6 h after drug withdrawal and were reversible, being no longer apparent after 24 h. These results suggest that long-term exposure of cerebellar granule cells to ganaxolone does not affect the sensitivity of the GABAAreceptor to several positive modulators. Nevertheless, the reduction in the amounts of the α1 and γ2 subunit mRNAs together with the increase in the abundance of the α4 subunit mRNA induced by abrupt discontinuation of long-term treatment with ganaxolone suggest that withdrawal of this drug might result in a reduced response to classic benzodiazepines.

Rat cerebellar granule cells were cultured for 5 days with progesterone, resulting in the conversion of progesterone to allopregnanolone, a potent and efficacious modulator of γ-aminobutyric acid (GABA) type-A receptors, as well as in decreases in the abundance of GABAAreceptor α1, α3, α5, and γ2subunit mRNAs. These effects were accompanied by decreases in the efficacies of diazepam and the β-carboline DMCM with regard to modulation of GABA-evoked Cl−currents. Withdrawal from such progesterone treatment resulted in a rapid and selective increase in the abundance of the GABAAα4subunit mRNA that was associated with a restoration of receptor sensitivity to the negative modulatory action of DMCM, a positive receptor response to flumazenil, and continued reduced responsiveness of receptors to diazepam. Prevention of allopregnanolone synthesis by the 5α-reductase inhibitor finasteride also prevented the changes in both GABAAreceptor gene expression and receptor function elicited by progesterone treatment and withdrawal.

Rat cerebellar granule cells were cultured for 5 days with progesterone, resulting in the conversion of progesterone to allopregnanolone, a potent and efficacious modulator of gamma-aminobutyric acid (GABA) type-A receptors, as well as in decreases in the abundance of GABA(A) receptor alpha(1), alpha(3), alpha(5), and gamma(2) subunit mRNAs. These effects were accompanied by decreases in the efficacies of diazepam and the beta-carboline DMCM with regard to modulation of GABA-evoked Cl(-) currents. Withdrawal from such progesterone treatment resulted in a rapid and selective increase in the abundance of the GABA(A) alpha(4) subunit mRNA that was associated with a restoration of receptor sensitivity to the negative modulatory action of DMCM, a positive receptor response to flumazenil, and continued reduced responsiveness of receptors to diazepam. Prevention of allopregnanolone synthesis by the 5alpha-reductase inhibitor finasteride also prevented the changes in both GABA(A) receptor gene expression and receptor function elicited by progesterone treatment and withdrawal.

The present study was designed to determine the effects of chronic neonatal exposure to the NMDA receptor antagonist phencyclidine (PCP) on [3H]MK-801 binding and on gene expression of NMDA receptor subunits in juvenile male rats. Rat pups were injected daily with PCP from day 5 to 15 and killed on day 21. [3H]MK-801 binding was measured by quantitative autoradiography. A sensitive RNase protection assay was employed to determine simultaneously the mRNA levels of NR1 subunit (comprising all different splice variants) and three NR2 subunits (NR2A-NR2C). The relative distribution profile of NMDA receptor subunits in the cerebral cortex was NR2B > NR1 > NR2A > NR2C and in the cerebellum NR2C = NR1 > NR2A = NR2B. Chronic PCP administration in postnatal rats produced significant reduction in both [3H]MK-801 binding and mRNA level of the NR2B subunit in the cerebral cortex. Expression of the other NMDA receptor subunits in the cerebral cortex did not change following the drug treatment. In the cerebellum, neither [3H]MK-801 binding nor any of the NMDA receptor subunit expression levels showed any alteration. Together, these data provide a molecular correlate for chronic postnatal PCP-induced down-regulation of [3H]MK-801 binding in rat cerebral cortex and suggest that the NR2B subunit plays an important role in developmental plasticity.

Basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) are two neurotrophic factors that play a role in neuronal maintenance and repair. The identification and characterization of mechanisms regulating neurotrophic factor availability in the central nervous system are vital to the development of therapeutic tools for prevention of neuronal degeneration. The lipophilic beta-adrenergic receptor (BAR) agonist clenbuterol was used to assess whether activation of central BAR changes the levels of NGF and bFGF mRNA. Within 5 hr, clenbuterol (10 mg/kg, intraperitoneally) elicited a 2-3-fold increase in bFGF and NGF mRNA content in rat cerebral cortex. The induction of bFGF and NGF mRNA expression showed anatomical specificity. Among the various brain areas examined, bFGF mRNA levels were increased in the cerebral cortex, hippocampus, and cerebellum, whereas induction of NGF mRNA was observed only in the cerebral cortex. Isoproterenol, a BAR agonist that does not cross the blood-brain barrier, also elicited a 2-3-fold increase in bFGF and NGF mRNA in the cerebral cortex. Propranolol (5 mg/kg, intraperitoneally), a lipophilic BAR antagonist, blocked the induction of NGF and bFGF mRNA mediated by either isoproterenol or clenbuterol, whereas nadolol (5 mg/kg, intraperitoneally), a BAR antagonist that does not cross the blood-brain barrier, blocked only the effect of isoproterenol. Therefore, activation of both central and peripheral BAR play a role in the regulation of bFGF and NGF mRNA expression. Moreover, in adrenalectomized rats, isoproterenol failed to increase bFGF and NGF mRNA, whereas clenbuterol elicited a 2-fold increase in bFGF mRNA in the cortex and hippocampus. Our data suggest that both adrenal steroids and noradrenaline might regulate the availability of selective neurotrophic factors in the adult central nervous system.

We have previously reported that focally evoked limbic motor seizures rapidly increase levels of mRNA encoding nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) in specific limbic system areas of the adult rat brain. The present studies examined the effect of both minimal and maximal electroconvulsive shock, applied via corneal electrodes, on NGF and bFGF mRNA levels in several limbic (entorhinal cortex, hippocampus, olfactory bulb) and extralimbic (striatum and cerebellum) brain regions. By 5 h following limbic motor seizures induced by low-intensity (minimal) electroshock (LES) (0.2 s, 50-70 mA; three times over a 1-h period), bFGF mRNA was significantly increased in entorhinal cortex and hippocampus, but not in the other regions examined. In contrast, tonic extensor seizures evoked by maximal electroshock (MES) (0.2 s, 150 mA; three times over a 1-h period) were associated with a significant increase in bFGF mRNA in all limbic and extralimbic regions examined. In the same animals, increases in NGF mRNA were limited to entorhinal cortex and hippocampus. Adrenal steroids were not required for the seizure-induced increase in NGF or bFGF mRNAs, based on the finding that adrenalectomized rats exhibited electroshock-induced increases in both NGF and bFGF mRNAs equivalent to the increase observed in sham-operated rats. It is suggested that the increase in mRNA levels for the neurotrophic factors occurs selectively in those regions which are especially activated by the specific seizure model, and represents an adaptive response to repeated noninjurious neuronal stimulation. Copyright 1994, 1999 Academic Press

The goal of this study was to determine whether chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptors (NMDAR) was associated with an augmentation of the NMDAR polypeptide subunits in the mammalian cortical neurons. The results show that chronic ethanol treatment produced an increase in the R1 and R2B polypeptide subunits. The R2A subunit was not expressed in these neurons. Chronic NMDAR antagonist ((+)-3-2-(carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP)) treatment also increased the R1 and R2B polypeptide subunits. A similar increase was observed when ethanol and CPP were used in combination. Binding studies using [3H]MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclophenptan-5,10-imine maleate), a noncompetitive NMDAR antagonist, confirmed that concomitant exposure of ethanol and CPP up-regulated the NMDAR. Our results demonstrate for the first time that chronic ethanol treatment increased the NMDA receptor polypeptide subunit synthesis and that it was associated with an increase in [3H]MK-801 binding sites.

The goal of this study was to determine whether chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptors (NMDAR) was associated with an augmentation of the NMDAR polypeptide subunits in the mammalian cortical neurons. The results show that chronic ethanol treatment produced an increase in the R1 and R2B polypeptide subunits. The R2A subunit was not expressed in these neurons. Chronic NMDAR antagonist ((+)-3-2-(carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP)) treatment also increased the R1 and R2B polypeptide subunits. A similar increase was observed when ethanol and CPP were used in combination. Binding studies using [3H]MK-801 ((+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclophenptan-5,10-imine maleate), a noncompetitive NMDAR antagonist, confirmed that concomitant exposure of ethanol and CPP up-regulated the NMDAR. Our results demonstrate for the first time that chronic ethanol treatment increased the NMDA receptor polypeptide subunit synthesis and that it was associated with an increase in [3H]MK-801 binding sites.