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Subcutaneous implantable cardiac defibrillator (S–ICD) is a well–established alternative to transvenous defibrillator in patients with an indication for an ICD without the concomitant need of pacing. Despite the overall excellent performance of S–ICD, oversensing of cardiac and non–cardiac signals is still the main cause of inappropriate shocks (IS). We present a case of IS due to F–wave oversensing and QRS morphological variability related to compete atrio–ventricular (AV) block.A 77–year–old man was admitted to the Emergency Room reporting two episodes of defibrillator shock, identified by remote monitoring as IS due to F–wave oversensing during paroxysmal atrial flutter (Figure 1). His past medical history included paroxysmal atrial fibrillation and post–ischemic left ventricular (LV) dysfunction with left bundle branch block, treated in 2012 with cardiac resynchronization therapy and implantable defibrillator (CRT–D) with subsequent normalization of LV ejection fraction (EF). The LV stimulation was later deactivated due to phrenic capture unavoidable with device reprogramming; afterwards, the occurrence of aortic valve and lead endocarditis resulted in CRT–D system extraction. At that time, considering the persistence of normal LVEF even without LV stimulation, an S–ICD was then implanted in primary prevention. The ECG at the time of admission presented with a complete AV block (Figure 2A), not clearly evident at the remote monitoring report. Few hours later a new episode of atrial flutter occurred, reveling a variable QRS morphologies of ventricular rhythm (Figure 2B). A more careful analysis of device memory reveals a previous episode of AV block with variable QRS morphologies leading to SMART Pass filter disabling (Figure 3). A transvenous ICD with left bundle branch area stimulation was then successfully implanted and the patient was discharged at home after two days.To the best of our knowledge, this is the first described case of inappropriate S–ICD shock related to AV block. The unpredictable QRS morphology of an escape rhythm and the inability of S–ICD to store diagnostic data regarding bradyarrhythmia may limit our knowledge on the behavior of S–ICD in case of AV block. The occurrence of an IS should always prompt careful analysis of all available S–ECGs. Previous events of QRS morphology change and/or disabling of the SMART Pass filter should be regarded with suspicion, even if an AV bock is not overt evident.

PVL is a complication associated with the implantation of a prosthetic valve. Since surgical re–intervention has a high operative risk, percutaneous closure (PC) has emerged due to its reduced invasiveness and the development of dedicated materials. We describe the case of a 66–year–old man with a mechanical oscillating disc mitral prosthesis who was admitted for acute heart failure. An echo showed a left ventricle with normal motion and a postero–medial mitral PVL with significant regurgitation. A transoesophageal echo confirmed the PVL in the 5 o’clock viewing portal with severe regurgitation. After optimising the medical therapy and with no change in echo findings, a cardiac catheterisation showed persistent post–capillary pulmonary hypertension, and therefore PC of the PVL was scheduled. Given the postero–medial location of the PVL, a transseptal puncture was performed using a 8.5 Fr Agilis introducer (Terumo) with telescoping system of a 6 r. JR4 catheter. The PVL was passed through with a Terumo 0.035 J–shaped guide, but without managing to advance the catheter beyond the leak. The guide was therefore advanced into the abdominal aorta and an arteriovenous circuit was created, which allowed the catheter to be advanced beyond the PVL and a closure device (AVPIII 14/5,Abbott St.Jude) was positioned with anterograde placement, with a distal disc on the ventricular side. Obliteration of the PVL, interference with the prosthetic disc and high transprosthetic gradients were observed despite several attempts to relocate the AVP, which was therefore removed. A second procedure was performed at a distance, creating a similar arteriovenous circuit by using a long introducer (110cm–Cook) which was advanced from the femoral artery beyond the leak in the opposite direction. An AVPIII (12/5) with a distal disc on the atrial side was positioned, this time with retrograde placement, with effective closure of the PVL and minimal residual regurgitation, without interference with the prosthesis. The course was free of complications; after one month the echo confirmed the result. Transcatheter closure of the PVL is a complex procedure, but relatively safe in experienced hands. This case is of particular interest due to the difficulty presented by the location of the PVL, which required measures of high technical complexity and because it describes a possible complication of the procedure, which was resolved by the simple reversal of the placement of the device.

A 12–year–old patient with paucisymptomatic SARS–COV2 infection in November 2020 with negative swab after 10 days. After 3 weeks access to pediatric emergency room for fever, maculo–papular rash on the trunk, conjunctivitis, nausea and abdominal pain: evidence of thrombocytopenia, increased CPK, LDH, AST and inflammation markers. She starts antibiotic therapy for suspected sepsis. After 24 hours asthenia, general illness, hypotension and tachycardia: echocardium with diffuse hypokinesia of the left ventricle (EF 35%); worsening of thrombocytopenia, D–Dimer, BNP and CPK increase, hyponatremia, troponin positivity, ATIII reduction; negative viral markers. On the basis of the most recent literature, the diagnosis of MIS–C is made, a post–infection SARS–COV2 multisystemic inflammatory syndrome. After discussion with the 3rd level SARS–COV2 Pediatric Center, the following therapy begins: iv diuretic, iv cortisone, sc heparin, iv immunoglobulins, Anakinra. For a progressive clinical worsening by cardiogenic shock with evolution to DIC, she is transferred by military plane to the pediatric intensive care of 3rd level SARS–COV2 Center. The patient is subjected to mechanical ventilation, therapy with inotropes (adrenaline and milrinone) and CRRT ultrafiltration in order to reduce the excessive levels of inflammatory mediators responsible for rapid multiorgan failure. After 4 days, haemodynamic parameters improvement (EF 50%); sartan and low dose diuretic have been started because of the presence of diastolic dysfunction. Discharge after 1 month of hospitalization with good clinical and haemodynamic stability. After 6 months from myocarditis onset with cardiogenic shock in MIS–C, cardiac MRI with evidence of EF 57% and small area of delayed enhancement on the anterior IVS with non–ischemic pattern, no longer present by imaging after 1 year by acute event. Currently the patient reports subjective well–being by the regular follow–up without arrhythmias by Holter monitoring. SARS–COV2 post–infection multisystemic inflammatory syndrome (MIS–C) represents a serious complication with possible myocardial involvement also following a paucysymptomatic infection as in the described case. What happened shows us that SARS–COV2 infection is still a devious clinical entity that needs close follow–up in the short and long term.

Takotsubo syndrome (TTS) is a cardiomyopathy induced by physical and/or emotional stress, characterised by transient changes of the regional motion generally extending beyond the territory distribution of one single coronary vessel. The classic form of TTS presents, in 43.7% of cases, with ST segment elevation and in about 80% with cardiac apical ballooning. In 1.5% of TTS cases, however, regional changes in motion are observed which may mimic an acute coronary syndrome. We describe the case of a 77–year–old woman with hypertension and hypercholesterolemia. The patient came to the ER due to polytrauma secondary to an accidental fall. During hospitalisation, the patient complained of a sudden onset of a retrosternal aching chest pain radiating to the back and right shoulder, associated with neurovegetative symptoms. An electrocardiogram showed a normofrequent sinus rhythm and T–negative waves in the infero–lateral region. Upon cardiology consultation, a transthoracic echocardiogram was performed showing a left ventricle with akinesia of the middle and apical segments of the inferolateral wall with compensatory hyperkinesis of the other segments. When an acute coronary syndrome was suspected, urgent coronary imaging was performed, showing coronary arteries without significant stenosis, while ventriculography confirmed the alterations in ventricular motion. Blood chemistry tests showed a phasic increase in myocardial necrosis enzymes and, in particular, in HS troponin values (max value 2714 ng/L). Therapy with an ace–inhibitor and a beta blocker was introduced; seriate echocardiographic controls showed a progressive normalisation of the alterations in motion. A TTS diagnosis was therefore made, according to InterTAK 2018 diagnostic criteria. This case is of particular interest as it is a prime example of a rare variant of TTS: the clinical presentation, the ECG alterations and the regional akinesia may lead to a clinical suspicion of ACS. A good knowledge of the TTS, including the focal variant, enables the cardiologist to make a correct diagnosis and to initiate suitable therapy.

Aortic dissection (AD) is the tearing of the tunica intima of the aortic wall with creation of a false lumen. Type–A AD, in which the intimal flaps originates in the aortic tract proximal to the left subclavian artery, is a surgical emergency because – if left untreated – it has mortality rates as high as 1–2% every hour, from the onset of symptoms. Certain collagenopathies, such as Marfan Syndrome, are a predisposing condition for AD. We describe the case of a 25–year–old man with Marfanoid habitus who came to the Emergency Room of our facility, with acute pulmonary oedema. He had been complaining about thoraco–abdominal pain, bloody mucus and worsening dyspnoea since the week before. Upon cardiology consultation, a transthoracic echocardiogram showed an aneurysm of the aortic root (70 mm) and the ascending aorta (90 mm), with dissection flap extended beneath the aortic valvular plane, with torrential aortic valve insufficiency and eccentric jet, a left ventricle severely dilated and a severe systolic dysfunction (EF 25%). On urgent CT angiography the dissection flap was observed to extend cranially to the right common carotid artery and caudally to the renal arteries. The patient then underwent cardiac surgery to replace the aortic valve with a mechanical prosthesis and the ascending aorta as per the Bentall procedure and to replace the aortic arch with reimplantation and debranching of the supra–aortic trunks. Four months after discharge, the patient presented again due to sustained ventricular tachycardia (SVT) which was interrupted by electric cardioversion. On this occasion, an ICD implant was indicated as a secondary prevention measure. After one month, recurrence of SVT was observed, which was successfully treated by the implanted ICD, and therefore indication was given for an electrophysiologic study and subsequent transcatheter radiofrequency ablation of the ventricular arrhythmia. The case presented is of particular interest as it highlights the crucial role of a rapid echocardiographic assessment focussed on making a diagnosis and directing treatment, despite a misleading clinical picture due to duration and atypicality of symptoms. It should also be stressed that an overall assessment of the patient, based on habitus and age, plays a major role in establishing a suspected diagnosis and guiding the patient towards the most appropriate treatment.

Arrhythmogenic cardiomyopathy (ACM) is characterised by myocardial structural alterations with fibro–adipose replacement/infiltration, most frequently affecting the right ventricle. Malignant arrhythmias represent the most dangerous clinical manifestation.We describe the case of a 38–year–old man who came to the Emergency Room of our hospital due to polytrauma. Following the unexpected ECG finding of signs of necrosis in the infero–lateral area and negative T waves in the antero–lateral area, a cardiological examination was performed. The patient, a smoker, had non–contributory family and personal history of cardiovascular diseases and sudden cardiac death. However, he reported several unspecified episodes of “absence seizures”. The transthoracic echocardiogram showed mild reduction in global left ventricular systolic function (EF 45–50%) due to regional changes in motion extending beyond the territory distribution of one single coronary vessel. Holter–ECG showed a Sustained Ventricular Tachycardia (SVT) symptomatic for syncope. A coronary angiography was therefore performed, which excluded any significant coronary stenosis and a cardiac MRI revealed the presence of fibro–adipose replacement of the left ventricle and, to a lesser extent, of the right side of the interventricular septum. Medical therapy with Bisoprolol, Ramipril, Spironolactone was initiated and an ICD was implanted as secondary prevention. No endomyocardial biopsy was carried out due to the high risk of the procedure; genetic testing proved to be negative. A diagnosis of borderline arrhythmogenic cardiomyopathy was therefore made. This case is of special interest as ACM with predominant left ventricular involvement (LDAC) is a rare cardiomyopathy. Diagnosis is made difficult by the presence of phenocopies and by the fact that the diagnostic criteria in use mostly focus on the forms with predominantly right–sided involvement. In the case of suspicious ECG changes, SVT or resuscitated cardiac death with imaging compatible with cardiomyopathy, it is important to raise the diagnostic suspicion of LDAC.

1. The purpose of this work was to ascertain whether the activation of caudal expiratory neurones located in the caudal part of the ventral respiratory group (VRG) may affect the pattern of breathing via medullary axon collaterals. 2. We used microinjections of DL‐homocysteic acid (DLH) to activate this population of neurones in pentobarbitone‐anaesthetized, vagotomized, paralysed and artificially ventilated cats. Both phrenic and abdominal nerve activities were monitored; extracellular recordings from medullary and upper cervical cord respiratory neurones were performed. 3. DLH (160 mM) microinjected (10‐30 nl for a total of 1.6‐4.8 nmol) into the caudal VRG, into sites where expiratory activity was encountered, provoked an intense and sustained activation of the expiratory motor output associated with a corresponding period of silence in phrenic nerve activity. During the progressive decline of the activation of abdominal motoneurones, rhythmic inspiratory activity resumed, displaying a decrease in frequency and a marked reduction or the complete suppression of postinspiratory activity as its most consistent features. 4. Medullary and upper cervical cord inspiratory neurones exhibited inhibitory responses consistent with those observed in phrenic nerve activity, while expiratory neurones in the caudal VRG on the side contralateral to the injection showed excitation patterns similar to those of abdominal motoneurones. On the other hand, in correspondence to expiratory motor output activation, expiratory neurones of the Bötzinger complex displayed tonic discharges whose intensity was markedly lower than the peak level of control breaths. 5. Bilateral lignocaine blockades of neural transmission at C2‐C3 affecting the expiratory and, to a varying extent, the inspiratory bulbospinal pathways as well as spinal cord transections at C2‐C3 or C1‐C2, did not suppress the inhibitory effect on inspiratory neurones of either the ipsi‐ or contralateral VRG in response to DLH microinjections into the caudal VRG. 6. The results show that neurones within the column of caudal VRG expiratory neurones promote inhibitory effects on phrenic nerve activity and resetting of the respiratory rhythm. We suggest that these effects are mediated by medullary bulbospinal expiratory neurones, which may, therefore, have a function in the control of breathing through medullary axon collaterals.

By using Vogel's method to test the anxiolytic action of benzodiazepines and reducing the intensity of the current delivered to the drinking tube, it is possible to distinguish the pharmacological activity of three types of ligands for the benzodiazepine recognition site. An anticonflict action typical of anxiolytic benzodiazepines, a proconflict action typical of many beta-carbolines, including FG 7142 (beta-carboline-3-carboxylic acid ethyl ester methyl amide), and an antagonistic action of the proconflict and anticonflict actions typical of RO 15-1788 (ethyl-8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-alpha]-[1, 4]-benzodiazepine-3-carboxylate) and CGS 8216 (2-phenylpyrazolo[4,3-c]quinolin-3-(5H)-one). Pentylenetetrazole, which causes convulsions by interacting with a subunit of the gamma-aminobutyric acid receptor that is different from the benzodiazepine recognition site, also induces a proconflict action that is antagonized by anxiolytic benzodiazepines but not by RO 15-1788.

The role of tau-aminobutyric acid (GABA)A receptors and of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors was studied in the pentylenetetrazol (PTZ) kindling model. The repeated administration of subconvulsant doses of PTZ (30 mg/kg i.p., 3 times a week for up to 10 weeks) produced chemical kindling in 80% of rats under treatment. PTZ kindling was associated with a decrease in GABA-mediated inhibition in the central nervous system. Thus, the binding of [3H]GABA, the binding of 35S-t-butylbicyclophosphorothionate and the GABA-stimulated uptake of 36Cl- were significantly decreased in the cerebral cortex of PTZ-kindled rats as compared with control rats chronically treated with saline. Moreover, PTZ-kindled rats showed a persistent increase in the sensitivity to the convulsant action of different GABA function inhibitors, such as isonicotinic acid hydrazide (120 mg/kg s.c.), picrotoxin (1.5 mg/kg i.p.), bicuculline (1.3 mg/kg s.c.), FG 7142 (N-methyl-beta-carboline-3-carboxamide; 20 mg/kg i.p.) and Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H- imidazo-(1,5-a) (1,4)-benzodiaze pine-3-carboxylate; 20 mg/kg i.p.). The pretreatment with the noncompetitive NMDA receptor antagonist, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate; 0.1-1.0 mg/kg i.p., 40 min before each injection of PTZ], prevented in a concentration-dependent manner the development of kindling and the increase in the responsiveness to the convulsant effects of GABA function inhibitors observed in PTZ-kindled rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The oxidative deamination of Cystamine (Cys) and Se-cystamine (Secys) catalyzed by Euphorbia characias diamine oxidase (ELAO) has been studied for the possible metabolic reactions in comparison with diamine oxidase from different sources. The results indicate that Cys and Secys are good substrates for ELAO. The oxidative deamination of Cys and Secys gives as first products the cystaldimine and Se-cystaldimine, respectively.The final products of Cys and Secys degradation are ammonia, elemental sulfur or selenium, and two-carbon compounds (C2).

A brain polypeptide termed diazepam-binding inhibitor (DBI) and thought to be chemically and functionally related to the endogenous effector of the benzodiazepine recognition site was purified to homogeneity. This peptide gives a single band of protein on NaDodSO4 and acidic urea gel electrophoresis. A single UV-absorbing peak was obtained by HPLC using three different columns and solvent systems. DBI has a molecular mass of approximately equal to 11,000 daltons. Carboxyl-terminus analysis shows that tyrosine is the only residue while the amino-terminus was blocked. Cyanogen bromide treatment of DBI yields three polypeptide fragments, and the sequences of two of them have been determined for a total of 45 amino acids. DBI is a competitive inhibitor for the binding of [3H]diazepam, [3H]flunitrazepam, beta-[3H]carboline propyl esters, and 3H-labeled Ro 15-1788. The Ki for [3H]-diazepam and beta-[3H]carboline binding were 4 and 1 microM, respectively. Doses of DBI that inhibited [3H]diazepam binding by greater than 50% fail to change [3H]etorphine, gamma-amino[3H]butyric acid, [3H]-quinuclidinyl benzilate, [3H]dihydroalprenolol, [3H]adenosine, and [3H]imipramine binding tested at their respective Kd values. DBI injected intraventricularly at doses of 5-10 nmol completely reversed the anticonflict action of diazepam on unpunished drinking and, similar to the anxiety-inducing beta-carboline derivative FG 7142 (beta-carboline-3-carboxylic acid methyl ester), facilitated the shock-induced suppression of drinking by lowering the threshold for this response.

Abstract: In frozen‐thawed repeatedly washed rat cortical synaptic membranes, Ca2+(1–5 mM) decreased the binding of [3H]muscimol whereas it increased the binding of [3H]γ‐aminobutyric acid (GABA). However, the binding of [3H]GABA was decreased by the same extent as the binding of [3H]muscimol when the membranes were incubated with baclofen (a selective ligand for the GABABbinding site) and Ca2+. Scatchard analysis of [3H]mus‐cimol binding revealed that Ca2+reduced the density of GABA binding sites without affecting the dissociation constant. Ca2+was more potent than Ba2+, Mg2+was ineffective, and the Ca2+antagonist La3+stimulated 3H]muscimol binding. The inhibition of [3H]muscimol binding by Ca2+was not influenced by calmodulin (50 μg/ml), trifluoperazine (10‐‐5M), verapamil (10‐‐6M), quinacrine (10‐‐4M), cordycepin (0.1 mM), leupeptin (20 μM), or soybean trypsin inhibitor (0.1 mg/ml). Moreover, the effect of Ca2+was additive to that of GABA‐modulin. These results indicate that Ca2+decreases the number of GABAAbinding sites while unveiling GABABbinding sites.

The present study was designed to examine the ability of felbamate, a novel antiepileptic agent, to antagonize the increase in seizure severity (i.e., chemical kindling) produced by chronic treatment with initially subconvulsant doses of pentylenetetrazol (PTZ). Rats were treated with PTZ (30 mg/kg, i.p., three times a week) for 8 consecutive weeks. Two other groups of rats received felbamate (300 or 400 mg/kg, i.p.), 90 min before each dose of PTZ. Pretreatment with felbamate at either dose prevented the progression of rank of seizures during chronic treatment with PTZ. Thus, the mean seizure score by the end of the chronic treatment (0–5 scale) was 0 in vehicle treated controls, 3.3 in rats treated with PTZ alone, 1.5 in rats treated with PTZ plus felbamate (300 mg/kg, i.p.) and 0.9 in the group treated with PTZ plus felbamate (400 mg/kg, i.p.). Felbamate also antagonized the long-term increase in the sensitivity to the convulsant effects of GABA function inhibitors observed in PTZ-kindled rats. Thus, the administration of a challenge dose of isoniazid (120 mg/kg, s.c.), picrotoxin (1.5 mg/kg, i.p.) or PTZ itself (15 mg/kg, i.p.), 15 to 45 days after the end of the chronic treatment regimen, induced convulsions in > 80% of PTZ-kindled rats and in < 20% of rats treated with PTZ + felbamate (400 mg/kg). The results are discussed in terms of the multiple mechanisms that can contribute to the anticonvulsant action of felbamate in the PTZ kindling model of epilepsy.

gamma-Aminobutyric acid (GABA)-modulin is a brain neuropeptide that appears to modulate specific high-affinity (20 nM) GABA recognition sites in brain. When added to crude synaptic membranes this peptide inhibits binding of [3H]GABA to the high-affinity site and prevents facilitation of [3H]diazepam binding elicited by GABA. GABA-modulin has been purified to homogeneity by ammonium sulfate precipitation, gel chromatography, and reverse-phase HPLC. Homogeneity was confirmed by a variety of means, including chromatography under four different HPLC conditions, two different polyacrylamide gel electrophoreses, and end group analysis. Purified GABA-modulin contains approximately 126 amino acids and has a molecular weight of 16,500. The GABA-modulin molecule contains an abundance of hydrophilic basic residues, and neither cysteine nor GABA is present. End group analyses of GABA-modulin showed that histidine is the free COOH terminus and the NH2 terminus is blocked. GABA-modulin specifically blocked both [3H]GABA binding to synaptic membranes (IC50, 0.5 microM) and GABA-stimulated [3H]diazepam binding; the binding of [3H]GABA to low-affinity sites was not affected.

1. Efferent intercostal α and γ activity and afferent intercostal muscle spindle activity were studied in decerebrate cats in response to stimulation of the anterior lobe of the cerebellum and to postural and other reflexes.

Haemocyanin from the lobster Palinurus elephas has been shown to change in its subunit composition according to the time of year. In contrast, in Palinurus mauritanicus, a lobster living at greater depth, no seasonal changes in subunit composition have been observed. The results obtained from a set of experiments performed on some Palinurus mauritanicus acclimatized in an aquarium have clearly indicated that modifications of haemocyanin subunit composition may be involved in the adaptation of arthropods to environmental change.

The bilateral intrastriatal injection of kainic acid (2 µg/caudate) caused a marked decrease in the activity of striatal dopamine-sensitive adenylate cyclase. This probable loss of target cells for dopamine was associated with a parallel decrease of the cGMP level in the cerebellar cortex, which was maximal (80% loss) by 24 h and prevented apomorphine from raising cerebellar cGMP levels. On the contrary harmaline and isoniazid both increased the levels of cerebellar cGMP in kainic-lesioned rats to the same extent as in control rats. The results indicate that dopamine mechanisms in the striatum are involved in the regulation of cerebellar cortex cGMP.