Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons.

AIMS: The crucial step in the pathogenic events that lead to the development and the progression of multiple sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate-mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MS patients. METHODS: A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and nonactive (na) relapsing remitting MS patients. Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells. RESULTS: Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase in glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects. CONCLUSION: These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF-mediated mechanisms of glutamate excitotoxicity in central neurons.

Therapeutic management of idiopathic recurrent serositis: a retrospective study.

OBJECTIVE: Idiopathic recurrent serositis (IRS) is the most frequent serositis encountered in real-life medical sceneries, and its management represents a therapeutic challenge. There are few epidemiologic data related to IRS, though most studies have focused on recurrent pericarditis, revealing that 70% of all forms of pericarditis are idiopathic and caused by innate immunity abnormalities. The aim of this study was to evaluate outcome and recurrence rates of patients with IRS, assessing management modalities used in our Periodic Fever Centre of the Gemelli Hospital, Rome, Italy, in comparison with previous treatments in other centres. PATIENTS AND METHODS: Retrospectively, we analyzed the medical charts of 57 unselected patients with history of IRS managed during the period 1998-2017. RESULTS: A strong heterogeneity emerged by evaluating treatments of this cohort. In particular, in our Centre there was a larger use of combined therapies: 14 patients out of 27 (52%) were treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine, compared to only 2 patients (7.4%) previously treated with combined treatments. We used corticosteroid monotherapy only in 1 case, against 7 from other centres. The mean duration of NSAID treatment in other hospitals was 43.8 days (SD ±27.40) and 191.25 days (SD ±42.23) in our Centre; the mean duration of corticosteroid treatment in other hospitals was 101.5 days (SD ±56.40) and 180.7 days (SD ±84.87) in our Centre. Colchicine was administered in other hospitals for the same duration of NSAIDs, and corticosteroids with an average duration of 111 days (SD ±30); conversely, we administered colchicine for an average duration of 250.12 days (SD ±80.7). Relapses of IRS were reported in 1/3 of cases who had discontinued therapies. CONCLUSIONS: The overall duration of treatments to manage IRS has a weight in terms of patients' outcome. A reduced duration of therapy with corticosteroids and a longer duration of therapy with NSAIDs determine a longer disease-free interval. A significant discriminating effect in terms of risk of IRS recurrence relies in an earlier combination therapy with colchicine independently from the start with either NSAIDs or corticosteroids. Finally, the evaluation of genes causing autoinflammatory diseases has not revealed any pathogenetic variants in a subcohort of 20/57 patients with IRS.

A novel crosstalk within the endocannabinoid system controls GABA transmission in the striatum.

The N-palmitoylethanolamine (PEA) is an endogenous member of the endocannabinoid system (ECS) with several biological functions, including a neuromodulatory activity in the central nervous system. To shed light on the neuronal function of PEA, we investigated its involvement in the control of both excitatory and inhibitory transmission in the murine striatum, a brain region strongly modulated by the ECS. By means of electrophysiological recordings, we showed that PEA modulates inhibitory synaptic transmission, through activation of GPR55 receptors, promoting a transient increase of GABAergic spontaneous inhibitory postsynaptic current (sIPSC) frequency. The subsequently rundown effect on sIPSC frequency was secondary to the delayed stimulation of presynaptic cannabinoid CB1 receptors (CB1Rs) by the endocannabinoid 2-AG, whose synthesis was stimulated by PEA on postsynaptic neurons. Our results indicate that PEA, acting on GPR55, enhances GABA transmission in the striatum, and triggers a parallel synthesis of 2-AG at the postsynaptic site, that in turn acts in a retrograde manner to inhibit GABA release through the stimulation of presynaptic CB1Rs. This electrophysiological study identifies a previously unrecognized function of PEA and of GPR55, demonstrating that GABAergic transmission is under the control of this compound and revealing that PEA modulates the release of the endocannabinoid 2-AG.

Prognostic significance of atrial fibrillation in thrombolysed and non thrombolysed patients.

AIM: Atrial fibrillation (AF) is considered a frequent complication of acute myocardial infarction (AMI). The aim of this study was to examine the incidence and prognostic significance of AF complicating AMI. METHODS: A total of 848 patients with AMI were examined evaluating: age, sex, coronary risk factors, incidence of AF, prior ischemic events, infarct location, electrocardiogram on admission, thrombolytic therapy, in-hospital complications and mortality. RESULTS: AF was recorded in 84 patients (9.9%). They were older (P<0.0001), less frequently smokers (P<0.007), had higher creatinekinase level (P<0.005) and more advanced heart failure (Killip class >or=2). AF was documented in non-thrombolysed more than in thrombolysed patients (11.2% vs 7.5%). Overall mortality resulted significantly higher in patients with AF (P=0.001); nevertheless it did not result as independent predictor of mortality. Instead, independent predictors of mortality have been Killip class >or= II (P<0.0001), age (P<0.0001) and prior infarction (P<0.002 ). CONCLUSIONS: In our experience, AF cannot be considered an independent predictor of mortality. Contrary, advanced heart failure, either in thrombolysed or not-thrombolysed patients, is an independent predictor of AF and mortality. Nevertheless, AF represents an expression of advanced heart failure, that is worsened by the development of arrhythmia with severe consequences on prognosis.

microRNAs Modulate Spatial Memory in the Hippocampus and in the Ventral Striatum in a Region-Specific Manner.

MicroRNAs are endogenous, noncoding RNAs crucial for the post-transcriptional regulation of gene expression. Their role in spatial memory formation, however, is poorly explored. In this study, we analyzed learning-induced microRNA expression in the hippocampus and in the ventral striatum. Among miRNAs specifically downregulated by spatial training, we focused on the hippocampus-specific miR-324-5p and the ventral striatum-specific miR-24. In vivo overexpression of the two miRNAs demonstrated that miR-324-5p is able to impair memory if administered in the hippocampus but not in the ventral striatum, while the opposite is true for miR-24. Overall, these findings demonstrate a causal relationship between miRNA expression changes and spatial memory formation. Furthermore, they provide support for a regional dissociation in the post-transcriptional processes underlying spatial memory in the two brain structures analyzed.

Doppler-derived mitral deceleration time of early filling as a strong predictor of pulmonary capillary wedge pressure in postinfarction patients with left ventricular systolic dysfunction.

OBJECTIVES: The aim of this study was to investigate the correlations between Doppler-derived transmitral flow velocity variables and pulmonary capillary wedge pressure in patients with severe left ventricular systolic dysfunction. BACKGROUND: Abnormal relaxation and increased chamber stiffness have opposing effects on the left ventricular filling pattern. When both abnormalities are present at the same time, as often occurs in patients with systolic dysfunction, the ability of Doppler recording to assess diastolic function and predict left ventricular filling pressure may be significantly compromised. METHOD: Pulmonary capillary wedge pressure and Doppler transmitral flow velocity profile were simultaneously recorded in 140 postinfarction patients with ejection fraction < or = 35%. RESULTS: Correlation between the ratio of mitral peak flow velocity in early diastole to peak flow velocity in late diastole (E/A ratio) and pulmonary capillary wedge pressure was weak (r = 0.65). Although the specificity of E/A > or = 2 in predicting > or = 20 mm Hg in pulmonary capillary wedge pressure was high (99%), its sensitivity was low (43%). Conversely, a very close negative correlation was found between mitral deceleration time of early filling and pulmonary capillary wedge pressure (r = -0.90). Sensitivity and specificity of < or = 120 ms in deceleration time in predicting > or = 20 mm Hg in pulmonary capillary wedge pressure were 100% and 99%, respectively. CONCLUSIONS: Doppler-derived mitral deceleration time of early filling provides a simple and accurate means of estimating pulmonary capillary wedge pressure that is particularly useful in patients with a normal or normalized mitral flow velocity pattern.

Influence of left ventricular cavity dimension on electrocardiographic estimation of the extent of wall motion abnormalities.

To estimate the influence of left ventricular cavity dimension on the electrocardiographic estimation of the extent of wall motion abnormalities, two-dimensional echocardiograms and standard 12-lead electrocardiograms (ECG) were carried out on 221 patients within 3 months after acute myocardial infarction (MI). Among the patients with anterior MI (96 patients; 43.4%) both the extent of asynergy (% of asynergic segments, an echo index taking into account the type of asynergy) and the electrocardiographic signs of necrosis (number of Q waves greater than or equal to 40 ms, Wagner's score) were significantly greater (p less than 0.001) in those with left ventricular dilatation (60 patients) than in those with normal ventricular size (36 patients); within the latter group, the ECG-asynergy correlations were good (r value 0.67-0.79). In patients with left ventricular dilatation no correlation was found. In inferior MI (108 patients, 48.9%), asynergy was more extensive in patients with left ventricular dilatation (p less than 0.001) than in those with normal left ventricle. However, the electrocardiographic extent of necrosis was similar in the two groups and no significant ECG-asynergy correlation was found. Likewise, in anteroinferior MI (17 patients; 7.7%), the ECG-asynergy correlations were statistically insignificant in both groups. In conclusion, the electrocardiographic patterns of necrosis are poorly related to the extent of asynergy and are greatly influenced by left ventricular dimensions.

Haemodynamic implications of exercise-induced myocardial ischaemia in patients with recent inferior myocardial infarction.

UNLABELLED: Two hundred and forty patients with recent inferior myocardial infarction were studied by a symptom-limited ergometric test with haemodynamic monitoring (triple lumen tip-thermistor Swan-Ganz catheter) in order to investigate and quantify the haemodynamic effects of exercise-induced myocardial ischaemia in post-infarct patients and to assess whether the ST-segment changes give any indication of the degree of ventricular impairment. One hundred and thirteen patients showed no ST-segment changes during excercise; ST-segment elevation in leads with abnormal Q wave occurred in 14 patients, ST-segment depression was recorded in 88 subjects, and both ST-segment elevation and depression were found in 27 patients. In subjects with no ST-segment shift, as well as in those with exercise-induced ST-segment elevation, the resting and exertional haemodynamic patterns were normal or nearly normal. In subjects showing ST-segment depression or both ST-segment elevation and depression during exercise the mean pulmonary wedge pressure was abnormally elevated (at peak exercise 25 +/- 8 and 24 +/- 7 mm Hg, respectively). However, 31% of these showed a normal haemodynamic pattern either at rest or during exercise. The number of leads with ST-segment depression and the sum of ST-segment depressions in standard ECG does not reliably indicate the degree of ischaemia-dependent left ventricular impairment. In contrast, in patients grouped on the basis of time of ST depression appearance, the lower the ischaemic threshold the more severe was the left ventricular impairment. Finally, to assess the relative role of both scar and ischaemia in producing left ventricular dysfunction, the haemodynamic patterns of patients with and without exercise-induced ST-segment depression were compared in subsets with similar echocardiographic wall asynergy extent (inferior, infero-apical, infero-septo-apical). Among patients with small or medium-sized scar, the exertional left ventricular filling pressure was normal in patients with no ST-segment depression and abnormally elevated in those with ST-segment depression. In patients with large infarct, the exercise pulmonary wedge pressure was similarly elevated in both the ischaemic and non-ischaemic group, but in the latter cardiac output increase during exercise was limited. IN CONCLUSION: in patients with recent inferior myocardial infarction exercise-induced ST-segment depression is a marker of left ventricular impairment when the ischaemic threshold is low. The impairment consists of an abnormal elevation of left ventricular filling pressure in all subjects, associated with a reduced increase in cardiac output in patients with large infarct.

The anaerobic index: uses and limitations in the assessment of heart failure.

Limitation of exercise tolerance is a hallmark of heart failure. Anaerobic threshold is a quantitative, reproducible, nonmotivational, submaximal index of exercise tolerance. The pathophysiological significance and methods of determination of anaerobic threshold are matters of debate. The principal aspects of such problems are discussed in this paper.

[Non-invasive recording of the His bundle electrogram: choice of leads and reliability of the "averaging" technic]. / Riconoscimento non invasivo dell'elettrogramma hisiano: scelta delle derivazioni e attendibilità della tecnica di "averaging".

An improvement in detecting His bundle activity using a Marquette high resolution Mac unit, without pharmacologic depression of AV node conduction, was obtained with two surface lead systems, which were selected on the basis of the His bundle anatomical position and its electrostimulation axis. In 8 patients the direction of the His bundle bipolar stimulation vector was evaluated in the frontal plane, on the orthogonal leads and with map of the chest potential. In 39 patients the surface recording, using high-gain amplification, filtering between 50-300 Hz and an averaging of 256-512 cycles, was obtained by positioning the electrodes in the following sites: manubrium sterni-xiphisternum-V4. When this lead system failed, it was replaced by another one, which included V4-right sternal and right vertebral border at the level of the 3rd intercostal space. In 24 patients (PR less than 0.16" in 4 cases) intracavitary and surface H-V recording were compared. The surface interval was measured between the apex of the surface "blip" and onset of the QRS. Sensitivity was 86% with a good correlation (r = 0.94) between invasive and non-invasive measurements. The surface leads, in which the His bundle activity was best detected, were the manubrium-xiphisternum (on the midsternal line) and V4-right vertebral border at the 3rd intercostal space level. Our external measurement technique avoids subjective misinterpretations; the surface H-V interval was on an average 6 msec. shorter than the invasive one. The upper normal value of non-invasive H-V interval is therefore 50 msec in our measurement method.

Metformin decreases platelet superoxide anion production in diabetic patients.

BACKGROUND: Patients with type 2 diabetes mellitus are usually treated with oral antidiabetic agents but it is still not known whether these drugs have antioxidant effects in humans. METHODS: We studied 60 patients with type 2 diabetes mellitus, divided into three groups on the basis of hypoglycaemic treatment (Group A: metformin, Group B: glibenclamide, Group C: diet). All patients were followed for at least 1 year. The three subgroups had similar clinical characteristics. Twenty healthy subjects, of comparable sex and age, were enrolled as controls. In each subject, platelet production of superoxide anion (O(2)(-)) elicited by collagen, was determined by lucigenin assay. RESULTS: Patients with diabetes had higher platelet O(2)(-) production than controls; no correlation was observed between blood glucose and platelet O(2)(-) production. Group A patients had platelet O(2)(-) production similar to that of healthy subjects but lower than Group B and Group C patients. CONCLUSION: The present findings suggest an in vivo antioxidant activity of metformin and warrant prospective studies to further explore this hypothesis.

Anxiety, depression, hunger and body composition: III. Their relationships in obese patients.

The present paper explores the relationships between anxiety, depression, hunger sensation and body composition in obese patients (OP). The aim is to detect whether or not there are abnormalities in these relationships in OP as compared to clinically healthy subjects (CHS). The study was performed on 22 CHS (2 M, 20 W; mean age = 24 +/- 2 years; mean body mass index = 21 +/- 2 kg/m2) and 48 OP (4 M, 44 W; mean age = 40 +/- 17 years; mean body mass index = 32 +/- 7 kg/m2). Anxiety and depression were found to be correlated, negatively, with the relative lean body mass, and, positively, with the fat body mass in OP but not in CHS. These findings corroborate the idea that anxiety and depression can reach an abnormal expression when obesity shows its worst loss in lean body mass and its highest expansion in adipocyte mass. As hunger sensation was found not to correlate with either anxiety or depression in OP, the opinion is expressed that the impairment of anxio-depressive integrity is a corollary of obesity rather than a primary affective disorder leading to obesity via an enhanced food intake.

Daily hunger sensation and body compartments: II. Their relationships in obese patients.

Hunger sensation (HS) is a signal whose levels change during the 24-h day. The daily mean level of HS was correlated with the human body compartments, as investigated by bioelectrical impedance analysis, to detect the relationship between the orectic perception and both the free fat mass (FFM) and the fat body mass (FBM) in 22 clinically healthy subjects (CHS) (2 M, 20 W, BMI: 18.5-24.0 kg/m2) and 48 obese patients (OP) (4 M, 44 W, BMI: 25.2-54.7 kg/m2). In CHS, the daily mean level of HS correlated positively with the FFM and negatively with the FBM. These correlations were not present in OP. This lack of relationships between HS and the body compartments where energy is maximally consumed (i.e., the FFM) and maximally stored (i.e., the FBM) indicates that the orectic response to energy expenditure and the orectic inhibition to fat accumulation are feedback mechanisms which are impaired in obesity.