Subclinical central inflammation is risk for RIS and CIS conversion to MS.

BACKGROUND: Subtle diffuse intrathecal inflammation is undetectable by conventional neuroimaging, and could influence multiple sclerosis (MS) disease course. OBJECTIVE: To explore the role of subclinical persisting intrathecal inflammation in radiologically isolated syndrome (RIS) or clinically isolated syndrome (CIS) conversion to MS, and in early MS disease reactivation. METHODS: One-hundred ninety-three subjects with RIS, CIS, relapsing-remitting (RR), or primary progressive (PP) MS were included, along with 76 matched controls. Cerebrospinal fluid (CSF) levels of interleukin-8 (IL-8), a major proinflammatory cytokine, were measured as a biomarker of intrathecal inflammation. Patients were followed up for 2 years. Clinical and imaging measures of disease progression were recorded. RESULTS: High central contents of IL-8 were associated to clinical progression in subjects with RIS, and to the risk of conversion to MS in subjects with CIS. Asymptomatic intrathecal inflammation placed subjects at risk for MS conversion, even regardless lesion load. CSF IL-8 levels were higher in RR MS with high disease activity. Higher number of relapses in the first two years since diagnosis and shorter first inter-attack intervals were observed in patients with high levels of IL-8. CONCLUSION: IL-8 might provide utility in determining the presence of active intrathecal inflammation, and could be important in diagnostically undefined cases.

NMDA receptor subunits are phosphorylated by activation of neurotrophin receptors in PSD of rat spinal cord.

We have investigated the distribution of NMDA and neurotrophin receptor systems and their reciprocal interactions in post-synaptic densities (PSD) purified from spinal cord. NMDA receptor subunits, trkA and trkB, but not trkC, were present in spinal cord PSD. The incubation of PSD with BDNF and NGF induced the phosphorylation of NR2A and B subunits. This phosphorylation was counteracted by antibodies directed against the catalytic domain of trkA and trkB receptors and by genistein. These results suggest the existence of a previously unexplored cross-talk between neurotrophins and NMDA receptors in rat spinal cord neurons.

[Recording of monophasic action potentials of the right ventricle in a case of long QT and isolated alternation of the U wave]. / Enregistrement des potentiels d'action monophasiques du ventricule droit dans un cas de QT long et alternance isolée de l'onde U.

Monophasic action potentials (MAP) of the right ventricle were recorded with suction electrodes in a case of long QTU, electrical alternans of the U wave and "torsades de pointe" by hypocalcaemia. Two electrophysiological features were observed:--a notable difference in the duration of MAPs of different zones of the right ventricle;--a change in the length and appearances of phase 3 of the longest MAPs with an inconstant bulge (delayed repolarisation) in the terminal portion of these same MAPs. These changes, which favourise focal reentry phenomena and/or reciprocal conduction are the probable explanation of the pathogenesis of episodes of "torsades de pointe". A reduction in the conductance of potassium associated or related to hypocalcaemia probably explains the second of the two changes.

[Efficacy of verapamil in the prevention of ventricular fibrillation in the acute phase of myocardial infarction]. / Efficacité du vérapamil dans la prévention de la fibrillation ventriculaire à la phase aiguë de l'infarctus du myocarde.

The effectiveness of verapamil in preventing ventricular fibrillation caused by coronary occlusion or reperfusion has been well demonstrated in animal studies, but these experimental data have not yet been confirmed in man. In this study we evaluated the prevalence of ventricular arrhythmias (fibrillation, sustained tachycardia and frequent extrasystoles) in patients hospitalized for myocardial infarction and treated with or without verapamil. The records of patients admitted to our Coronary Intensive Care unit during a 5-year period were analyzed retrospectively. Strict selection criteria enabled us to divide our patients into two homogeneous groups. The control group (group A) consisted of 106 patients who received only continuous infusions of heparin. The treated group (group B) comprised 89 patients who received exclusively verapamil by intravenous injections followed by continuous infusions. The prevalence of ventricular arrhythmia of all types was significantly lower in group B (22 p. 100) than in group A patients (71 p. 100; p less than 0.001). Episodes of ventricular fibrillation, in particular, were considerably less frequent in group B patients (1 p. 100) than in group A patients (13 p. 100; p less than 0.001). It would appear from these results that verapamil is highly effective in preventing death due to cardiac arrhythmia in the acute phase of myocardial infarction.

Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia.

We here present data on immune gene expression of chemokines, chemokine receptors, cytokines and regulatory T-cell (T-reg) markers in chronic patients suffering from either schizophrenia (SCZ, N=20) or bipolar disorder (BD=20) compared with healthy controls (HCs, N=20). We extracted RNA from peripheral blood mononuclear cells and performed real-time (RT)-PCR to measure mRNA levels of chemokines, chemokine receptors, cytokines and T-reg markers. All the analyses were Bonferroni-corrected. The classical monocyte activation (M1) markers il6, ccl3 were significantly increased in BD as compared with both HC and SCZ patients (P=0.03 and P=0.002; P=0.024 and P=0.021, respectively), whereas markers of alternative (M2) monocyte activation ccl1, ccl22 and il10 were coherently decreased (controls: P=0.01, P=0.001 and P=0.09; SCZ subjects: P=0.02, P=0.05 and P=0.011, respectively). Concerning T-cell markers, BD patients had compared with HC downregulated ccr5 (P=0.02) and upregulated il4 (P=0.04) and compared with both healthy and SCZ individuals downregulated ccl2 (P=0.006 and P=0.003) and tgfß (P=0.004 and P=0.007, respectively). No significant associations were found between any immune gene expression and clinical variables (prior hospitalizations, Brief Psychiatric Rating Scale, medications' dosages and lifetime administration). Although some markers are expressed by different immune cell types, these findings suggest a coherent increased M1/decrease M2 signature in the peripheral blood of BD patients with potential Th1/Th2 shift. In contrast, all the explored immune marker levels were preserved in SCZ. Further larger studies are needed to investigate the relevance of inflammatory response in BD, trying to correlate it to psychopathology, treatment and outcome measures and, possibly, to brain connectivity.

[Experimental characterization of propafenone. Hemodynamic effects]. / Caratterizzazione sperimentale del propafenone. Effetti emodinamici.

We studied the haemodynamic effects of Propafenon in a group of 20 subjects who had a coronary arteriography and a left ventriculography. The drug was been administered in doses of 1 mg/kg b.w. i.v. in 5 minutes. The haemodynamic parameters were measured in basal conditions and after 10 and 20 minutes. The basal data and those obtained after 20 minutes were analyzed and compared statistically. Our results show that Propafenon administered acutely i.v. in therapeutic doses causes a very small depression of cardiac inotropism. The same results were obtained in subjects whose basal haemodynamic parameters were abnormal. Our data show that the drug can be used safely also in subjects with mild heart failure.

Growth factors in pituitary tumors.

Prolactin-secreting tumors are the most frequently occurring neoplasms in the human pituitary. Although the clinical syndrome associated with prolactinomas is well recognized the molecular and cellular mechanisms leading to cell transformation and development of these tumors remain elusive. In this paper we summarize recent evidence suggesting that both hypothalamic and intrapituitary defects can be involved in the development of prolactinomas. In particular alterations of the hypothalamo-pituitary dopaminergic transmission result in the dysregulation of the proliferative activity of lactotrope cells leading to tumor development. Similarly changes in the expression and activity of resident growth factors also play a role in pituitary tumorigenesis. In particular both overexpression of TGF alpha and loss of NGF production appear to be involved in the development and progression of prolactin-secreting tumors.

[Effects of Bunaphtine on right atrial and ventricular monophasic action potentials in man. Preliminary note (author's transl)]. / L'effetto della Bunaftine sui potenziali d'azione monofasici del miocardio atriale e ventricolare destro nell'uomo. Nota preliminare

Effects of Bunaphtine on right atrial and ventricular monophasic action potentials were investigated in 6 patients using the technique of endocavitary recording with a suction electrode. The authors found that the drug, given intravenously in the usual therapeutic dosages, increases the total duration of MAP both atrial and ventricular, together with quite a proportional ERP prolongation. At ventricular level MAP's increase in correlated to a prevailing and strong increase of phase 3. However, the variations of the MAP's amplitude, its O dv/dt phase and the cardiac specific conduction's alterations (noted only at higher dosages) have been inconstant and poor on the whole. On the basis of these results, the mechanism of the action of the drug is discussed.

[A study of the mechanism of the action of Bunaphtine recording the myocardial monophasic action potentials in man. Conclusive report (author's transl)]. / Studio sul meccanismo d'azione della bunaftine mediante registrazione dei potenziali d'azione monofasici del miocardio nell'uomo. Nota conclusiva

In this paper the authors conclude their study of the mechanism of the action of Bunaphtine. Both atrial and ventricular MAP were recorded by a suction electrode in 13 patients before and after Bunaphtine (1.5-2 and 2.5 mg/Kg i.v.). With the lower dosages, the drug acts specifically on repolarization: it greatly increases the duration of MAP, together with a proportional ERP prolongation; the ERP/MAP ratio is not changed. With the higher dosages, there is a greater effect on the depolarization velocity (decrease of the O dv/dt phase of MAP) and on the conduction, this last being less evident. At the atrial level there is a conspicous ERP prolongation, with a remarkable increase of ERP/MAP ratio. There is full agreement between these results and those obtained experimentally on the dog and in vitro. Bunaphtine has therefore unquestionable antiarrhythmic properties and it can have a double action mechanism; with higher dosages its action-quinidine-like-is predominant at the atrial level.

[Ischemic and non ischemic electrophysiologic changes during selective coronary arteriography. Their role in the pathogenesis of the electrocardiographic changes and arrhythmias (author's transl)]. / Modificazioni elettrofisiologische di natura ischemica e non ischemica durante coronagrafia selecttiva. Lore ruolo nel determinismo dells modificazioni eletrocardiofrafiche e dell aritmie.

The results of a study made in mae recording the right ventricular monophasic action potential (RV MAP) by suction electrocatheter during coronary arteriography (35 cases) are reported. Normally, when no coronary spasm is present, coronary arteriography provokes a prolongation of MAP of the myocardial diffusion of the contrast medium. On the contrary in five cases, in which right coronary spasm occurred, modifications of a clear ischemic pattern were seen: a shortening of the RV MAP phase 2 in two cases; a reduction of the amplitude and rate of the RV MAP phase 0 in one case; both shortening of total duration of RV MAP and changes of its 0 phase in other two cases. The Authors compare these clinical observations with the experimental data and discuss the role of these different electrophysiological alterations in the pathogenesis of the electrocardiographic changes and arrhythmias.

Severity of arrhythmias and extent of hypertrophy in hypertrophic cardiomyopathy.

To evaluate the relationship between the extent of left ventricular hypertrophy and ventricular or atrial arrhythmias, 77 patients with hypertrophic cardiomyopathy underwent two-dimensional echocardiography and 24-hour Holter monitoring. Antiarrhythmic treatment was discontinued before the study. Hypertrophy was septal in 33 patients, "extensive" (i.e., involving the septum and free wall) in 38 patients, and predominantly apical in six patients. Lown grade I and II ventricular arrhythmias were detected in 37% of patients, grade III in 21%, and grade IV in 29%. Atrial extrasystoles were seen in 52% of patients and chronic atrial fibrillation in 13%. More serious ventricular arrhythmias (Lown grades III and IV) occurred significantly more frequently in patients with extensive than in those with only septal hypertrophy (22/38 vs 11/33; p less than 0.001); similarly, chronic atrial fibrillation occurred more commonly in those with extensive hypertrophy (9/38 vs 1/33; p less than 0.01). During a mean follow-up period of 2.6 years, three patients died. All had a pattern of extensive hypertrophy. Two of them had ventricular tachycardia and the third had chronic atrial fibrillation. Results of this study suggest that an echocardiographic finding of extensive hypertrophy represents a useful marker for detecting patients at increased risk for serious ventricular and atrial arrhythmias.

Nerve growth factor suppresses the tumoral phenotype of human prolactinomas.

We summarize here our data showing that various phenotypical characteristics distinguish prolactinoma cell lines obtained from responder and nonresponder patients, as defined by their responses to bromocriptine administration. Nonresponder cell lines have a higher degree of malignancy than responder cells and do not express D2 receptors for dopamine. Both cell lines express NGF receptors. Exposure of the most malignant nonresponder cell lines to NGF, both in vitro and when transplanted in vivo in nude mice, results in their differentiation into the responder phenotype reexpressing D2 receptors. Sequential administration of NGF and bromocriptine thus may be a promising therapy for patients refractory to bromocriptine.

[Junctional bradycardia and junctional non-paroxysmal tachycardia. A study with atrial and His electrogram and influence of neurovegetative system (author's transl)]. / Bradicardia giunzionale stabile e tachicardia giunzionale semplice non parossistica. Studio con l'elettrogramma atriale ed hissiano ed influenza delle stimolazioni neurovegetative

Two cases of unusual A-V nodal rythms, very slow junctional bradycardia and junctional non paroxysmal tachycardia, are described. The Authors emphasize the study of the His bundle electrograms, the atrial electrograms and the time of the intrinsecoid deflection for correct diagnosis of these dysrrhythmias. From the results of the clinical and electrofisiological study and neurovegetative responses some conclusions about the mechanism and clinical significance of these arrhythmias are drawn.

[Comparative study of the anti-arrhythmic activity of mexiletine and lidocaine in ventricular hyperkinetic arrhythmias]. / Studio comparativo tra l'efficacia antiaritmica della mexiletina e della lidocaina nelle aritmie ipercinetiche ventricolari.

The present study has been carried out on 50 patients admitted to C.C.U. for cardiovascular diseases of various ethiology (44 patients with ischemic heart disease) who required antiarrhythmic theory for different types of ventricular arrhythmias: monofocal ventricular extrasistoles greater than 6/min, bigeminal ventricular extrasistoles, polifocal and/or repetitive ventricular tachycardias. The patients have been randomly allocated into two groups of 25 subjects: the first one has been treated with Mexiletine and the second with Lidocaine. In Mexiletine treated group the following results have been obtained: 19 excellent (76%), 4 good (16%) and 2 ineffective (8%). In Lidocaine treated group: 11 excellent (44%), 5 good (20%) and 9 ineffective (36%). Statistical analysis by chi square test has shown significant prevalence of favourable results in Mexiletine treated patients (p less than 0.02; X(2) = 5.33). Moreover, in relation to the type of arrhythmias, Mexiletine succeded in a greater number of cases of complicated ventricular extrasistoles (bigeminal, polifocal and/or ripetitive) and in ventricular tachicardias. Mexiletine also has induced significant reduction of QTc and significant increase of cardiac rate, whereas it did not affect significantly the PR interval and blood pressure. None of these parameters has been influenced significantly by Lidocaine. Side effects have been similar for both drugs and generally mild. On the basis of results and in accord with the electrophysiological properties, the Authors discuss the possible mechanism of action and the role of Mexiletine in the treatment of ventricular arrhythmias particularly those complicating acute phase of myocardial infarction.

[Origin of the left circumflex coronary artery from the right Valsalva sinus. Two cases with clinical and instrumental signs of coronary insufficiency (author's transl)]. / Origine dell'arteria coronaria circonflessa sinistra dal seno di Valsalva di destra. A proposito di due casi con segni clinici e strumentali di insufficienza coronarica

Two cases of isolated anomalous origin of the left circumflex coronary artery from the right Valsalva sinus are described. In contrast with all the cases reported in the literature, both our female patients had typical angina; in one case, moreover, in coincidence with the precordial pain there were significant alterations of the repolarization, also caused by stress testing with the bicycle ergometer. On the basis of these findings, the authors believe that in patients with this anomaly the angina might be produced through a sharp decrease in the circumflex coronary artery blood flow correlated with caliber changes of the aorta.

[Identification using thoracic electromapping of patients with sustained postinfarct ventricular tachycardia. Preliminary results of a new method of analysis of ST-T isoarea maps]. / Identificazione mediante elettromappe toraciche di pazienti con tachicardia ventricolare sostenuta post-infartuale. Risultati preliminari di un nuovo metodo di analisi delle mappe isoaree di ST-T.

Recent studies have demonstrated that body surface maps (BSM) can be employed as non-invasive diagnostic tool for recognizing cardiac states at risk for repetitive ventricular arrhythmias in patients (pts) with old infarction. Our study reports preliminary results of a new method of statistical analysis of ST-T isoarea maps for identifying patients with post-infarction sustained ventricular tachycardia. 38 pts with previous myocardial infarction have been studied, 25 without and 13 with sustained ventricular tachycardia (VT). The two groups of pts did not differ significantly for age, site of infarction and ejection fraction. BSM have been recorded by means of an automated 35-channels instrument from 140 thoracic leads. For each lead ST-T deflection area has been calculated in microV.sec and taken as input variables for stepwise discriminant analysis which allowed identification of the integral values significantly discriminant (for F less than 0.15) between the two groups. Canonical analysis has been applied to identified values to obtain, by canonical coefficients, linear combination of the values for the highest correlation with the two groups of pts. To test the power of the method, the two groups of pts have been divided randomly in a learning set (17 pts without and 9 pts with VT) and a test set (8 pts without and 4 pts with VT).(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole.

OBJECTIVE: Our purpose was to study prospectively the pregnancy outcome after first-trimester exposure to fluconazole, an effective antifungal agent teratogenic in animals. STUDY DESIGN: We conducted a prospective cohort study of women who contacted three Italian teratogen information services. We compared the pregnancy outcomes of 226 women exposed to fluconazole with that of 452 women exposed to nonteratogenic agents, with use of logistic regression to control for potential confounders. RESULTS: Among the 226 pregnancies exposed to fluconazole there were 22 miscarriages, 1 stillbirth, and 7 infants with congenital anomalies. The prevalence of these outcomes and of neonatal growth parameters and the rate of neonatal complications were similar to those in the reference group. Women in the fluconazole group had a fivefold increased occurrence of induced abortions. CONCLUSIONS: First-trimester exposure to fluconazole does not appear to increase the prevalence of miscarriages, congenital anomalies, and low birth weight.

Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines.

Nerve growth factor (NGF) has antiproliferative and differentiating effects on adenomas of neuroendocrine origin. Cell lines derived from small-cell lung carcinoma (SCLC), a very aggressive neuroendocrine tumor, express NGF receptors. The role of NGF in the control of proliferation and progression of this carcinoma, however, has never been investigated. Chronic exposure of NCI-N-592 and GLC8 SCLC cell lines to NGF remarkably inhibited their proliferation rate both in vitro and in vivo, prevented their anchorage-independent clonal growth in soft agar, impaired their invasive capacity in vitro, and abolished their tumorigenic potential in nude mice. The proliferative response of SCLC cell lines to nicotine was also remarkably impaired by in vitro NGF treatment. Furthermore, NGF treatment activates in SCLC cell lines the expression and secretion of NGF. NGF thus reverts SCLC cell lines to a noninvasive, nontumorigenic phenotype that does not respond to nicotine and produces NGF.