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.

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.

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.

Prospective clinical evaluation and follow-up of a cohort of consecutive VT/VF patients, using a staged-care protocol, including coronary arteriography, programmed electrical stimulation and cardiac surgery.

The prospective evaluation and follow-up of 39 consecutive subjects with VT/VF, 6 of whom, with cardiac arrest (CA), are reported. Patients were enrolled in a specific staged-care approach protocol, which included coronary arteriography (CAR) and ventriculography (VC), in order to exclude the need of cardiac surgery, including coronary artery bypass graft (CABG), with and without left ventricular aneurysmectomy (LVA). The protocol included inducibility of VT/VF, which was verified by programmed electrical stimulation (PES) in control conditions and after antiarrhythmic therapy (ADT), to assess persistent inducibility and mainly to verify the hemodynamic sequelae of VT. VT that showed poor hemodynamic tolerance was treated with ICD, while well-tolerated VT was treated by ADT or ablation when indicated. Furthermore, PES was obtained after surgical procedures. As a first step, the patients were assigned to receive amiodarone (AMIO) (200-400 mg/daily) in the presence of EF% < 30% or contraindication to sotalol, (Group A), or sotalol (SOT) (80-140 mg/daily) in the presence of EF > or = 31%. (Group C). Conversely, in case of recurrences, patients were assigned to receive AMIO (200-300 mg/daily) plus metoprolol (MET) (20-100 mg/daily), (Group B) or, in case of intolerance to beta-blockers, to AMIO plus mexiletine (MEX) (200 mg/daily) (Group D). The four groups were similar for the type of VA, with recurrent ventricular tachycardia (RVT) being the most frequent one. The most frequent underlying cardiac disease of VA in this study was post-AMI CAD, with a rate of over 60% in all four groups. Single- and two-vessel lesions were found at CAR in various patients in all four groups, in 5/13 (38%) in Group A, in 8/14 (57%) in Group B, in 5/7 (71%) in Group C, and in 3/5 (60%) in Group D. Cardiac surgery was performed in a similar and limited number of patients in all four groups, in 4/13 (30%) in Group A, in 4/14 (35%) in Group B, in 2/7 (28%) in Group C, and in 2/5 (40%) in Group D. In 8/39 (20.5%) of the patients who underwent CABG, there was no operative or late mortality; 4/39 (10.2%) received CABG and LVA, and two died. For the amiodarone plus metoprolol and sotalol patients only, PES showed a lower residual inducibility, in comparison to the amiodarone and amiodarone + mexiletine groups. In the entire group, 7 out of 26 (27%) were still inducibile at PES while in 19/26 (64%) of the patients, an apparently effective treatment could be found, documenting the relative usefulness of PES. Recurrence rate was the highest in the amiodarone + mexiletine group and in patients with previous CA. Our data show the potential utility and limitations of ADT, even using the most effective antiarrhythmic drugs and association of drugs, mainly because of the high recurrence rate of VT observed in the present study, even in non-inducible patients [14/39 (36%)]. In conclusion, in a prospective and staged-care approach protocol of management of VT/VF patients, only a few patients with VT/VF benefited from cardiac surgery. PES could still play a role in the evaluation of the most effective ADT. Amiodarone + metoprolol seems to be the most effective ADT in these patients. Nevertheless, a high recurrence rate was observed in this patient population, even with an aggressive protocol, in the short follow-up period of 12 +/- 8 months, confirming recent data on the superiority of ICD to ADT, in patients with frequent recurrences or hemodynamically poorly-tolerated VT. In these patients, ICD therapy should definitively be preferred to ADT.

High vitamin A intake in early pregnancy and major malformations: a multicenter prospective controlled study.

The European Network of the Teratology Information Services (ENTIS) collected and evaluated data on 423 pregnancies exposed during the first 9 weeks of gestation to a "high" dose of vitamin A (10,000 IU per day or more). Data were collected prospectively; 394 women (93.1%) were followed by telephone interview up to the first few weeks after the expected date of delivery, using standardized procedures. The presence of major structural malformations, excluding chromosomal and genetic diseases, was evaluated in 311 infants exposed to a median daily dose of vitamin A of 50,000 IU per day (range, 10,000-300,000 IU per day; interquartile range, 25,000-60,000 IU per day). Three infants with a major malformation were reported: pulmonary stenosis, stenotic anus with fistula, and bilateral inguinal hernia. No congenital malformations were reported among 120 infants exposed to more than 50,000 IU per day of vitamin A. When the birth prevalence rate of major malformations in the study group was compared with two internal control groups of infants exposed to: 1) "high" vitamin A exposure later in pregnancy, and 2) nonteratogenic agent exposures, the rate ratio was, respectively, 0.28 (CI 95% interval, 0.06, 1.23) and 0.50 (CI 95% interval, 0.14, 1.76). The studied sample did not provide evidence for an increased risk of major malformations, associated with "high" vitamin A intake during the organogenetic period, higher than 2.76 above the control reference risk of 1.91% (power 80%, alpha 0.10).

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.

[Clinical characteristics, familial distribution and preliminary genetic data in 9 different families with "Brugada's syndrome"]. / Caratteristiche cliniche, distribuzione familiare e preliminari dati genetici in nove diverse famiglie con "sindrome di Brugada".

Clinical electrocardiographic evaluation and complete non-invasive assessment including nuclear magnetic resonance (NMR) are reported for 7 subjects with cardiac arrest (CA), 6 due to ventricular fibrillation (VF) and 1 to ventricular tachycardia (VT). Two more subjects, one with and one without a family history of non-resuscitated sudden death (NRSD), were included. All 9 subjects showed the typical pattern of the Brugada's syndrome (BS), characterized by incomplete right bundle branch block, ST T elevation in V1 V3. We globally evaluated 64 subjects belonging to the 9 families examined, 5 of whom were identified in Bologna, 3 in Florence and one in Parma. BS is characterized in the experience described in the present paper by a family distribution of the ECG pattern in different members. Furthermore, a family distribution of NRSD, even at a young age, was observed. Electrocardiographic features were consistent with variable degrees and aspects of the intraventricular conduction delay (ICD) and of the ST T elevation pattern. NMR has been performed so far in 23 out of 64 members examined by echo, and was normal in 17/23, with only 6 showing pathological aspects such as mild dilatation of the right ventricle, reduced thickness of the right free wall, isolated dilatation of the right ventricular infundibulum and other minor pathological aspects. Preliminary genetic screening (GS), performed on 20 members of three families, was negative for the typical genetic patterns of right ventricular dysplasia (ARVD). In six families, GS is still ongoing. Genetic screening of sodium channel pathology is in progress in the same families. In conclusion, BS has been documented in the present paper as a hereditary syndrome, both for clinical and ECG aspects, associated with CA due to VF, which required an AICD implantation, at least in symptomatic subjects. There may exist a CONGENITAL form of BS due to pathology of sodium channels, without a demonstrable structural heart disease and an ACQUIRED form of BS secondary to an initial ARVD. From the clinical point of view, a complete evaluation, including serial ECG, pharmacological testing and programmed electrical stimulation of other subjects in the families, may be important in preventing sudden death, mainly in symptomatic subjects who always require an implantable cardioverter defibrillator.

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.

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.

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.

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.

[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.

[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)

[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.

[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.

[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.

[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.

[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.