A PHACES syndrome unmasked by propranolol interruption in a tetralogy of Fallot patient: case report and extensive review on new indications of beta blockers.

Infantile hemangiomas (IHs) are the most common benign tumors of infancy and usually they don't require specific therapy. In 10-20% of cases IHs are able to generate complication and medical/surgical intervention is needed. For many decades standard treatment consisted in oral or intralesional corticosteroids until Leaute-Labreze and colleagues published the first report on the efficacy of propranolol for cutaneous infantile hemangiomas in 2008. IHs can be sometimes part of complex syndrome. Here we report the case of a patient with tetralogy of Fallot operated at 5 month of age who stopped propranolol treatment for hypoxic spells and unusually developed facial and subglottic IHs configuring the diagnosis of PHACES syndrome (posterior fossa brain malformations, hemangioma, arterial anomalies, cardiac defects and/or aortic coarctation, ocular anomalies and sternal defects). To our knowledge this is the first report in the international literature of a delayed appearance of an infantile hemangioma involving the skin and the airways (PHACES syndrome). The pathophysiological explanation relies on the mechanism of action of propranolol which seems to act initially with vasoconstriction, down-regulating proangiogenetic factors and inducing endothelial cell apoptosis. Many decades since their introduction ß-blockers are useful in a growing group of diseases. The pleiotropic effect of ß-adrenoceptors antagonists is not yet deeply understood, residing in neurohormonal regulation systems and angiogenesis and proving to be an effective treatment from cardiovascular to oncological illnesses.

CYP superfamily perturbation by diflubenzuron or acephate in different tissues of CD1 mice.

This work aimed to investigate whether the insecticide acephate (125 or 250 mg/kg b.w.) or diflubenzuron (752 or 1075 mg/kg b.w.), two of the most widely used pesticides worldwide, impairs CYP-linked murine metabolism in liver, kidney and lung microsomes after repeated (daily, for three consecutive days) i.p. administration. The regio- and stereo-selective hydroxylation of testosterone was used as multibiomarker of different CYP isoforms. Both gender and tissue specific effects were observed. Lung was the most responsive tissue to induction by lower diflubenzuron dose, as exemplified by the marked increase of testosterone 7alpha-hydroxylation (CYP2A) (up to 13-fold) in males. Higher dose produced a generalized inactivation. At the lower dose acephate induced 6beta- (CYP3A1/2, liver) as well as 2beta- (CYP2B1/2, kidney) hydroxylase activities ( approximately 5 and approximately 4-fold increase, respectively) in males. In females, a marked suppression of the various hydroxylations was observed. At 250 mg/kg of acephate, animals did not survive. Induction of the most affected isoforms was sustained by immunoblotting analysis. Corresponding human CYP modulations might disrupt normal physiological functions related to these enzymes. Furthermore, the co-mutagenic and promoting potential of these pesticides, phenomena linked to CYP upregulation (e.g. increased bioactivation of ubiquitous pollutants and generation of oxygen free radicals) are of concern for a more complete definition of their overall toxicological potential.

Genetic and metabolic effects of gluconasturtiin, a glucosinolate derived from cruciferae.

It is thought that induction of detoxifying phase-II drug metabolizing enzymes or inhibition of bioactivating phase-I by phytoalexins could protect against mutagens and neoplasia. In the search for potential naturally occurring molecular chemoprevention agents, particular attention has been devoted to isothiocyanates, which are breakdown products-via myrosinase-of glucosinolates such as gluconasturtiin (GNST), a natural constituent of cruciferae. Here, we first investigated the ability of GNST to modulate metabolizing enzymes in male Swiss Albino CD1 mice injected by gavage (24 mg/kg or 48 mg/kg b.w.) with GNST either in single or repeated (daily for four consecutive days) dose. Using selected probes to various cytochrome P450 (CYP) isoforms, a marked and generalized decrease of CYP content, NADPH-(CYP)-c-reductase and various CYP-linked monooxygenases (measuring CYP1A1, CYP2B1/2, CYP3A1/2, CYP1A2 and CYP2E1), was observed in hepatic, renal and pulmonary subcellular preparations (up to approximately 66% loss, liver). Similar behavior was recorded using the regio- and stereo-selective hydroxylation of testosterone as multibiomarker (CYP2A1 and CYP2B9, up to approximately 96% loss), as well as with the phase-II marker glutathione S-transferase (up to approximately 50% loss, liver). We also performed genotoxicity investigations, using the diploid D7 strain of yeast Saccharomyces cerevisiae as a biological test system. GNST was able to significantly induce point reverse mutation in growing cells without myrosinase, thus suggesting either a direct GNST or a CYP-linked metabolite role in the genotoxic response. On the contrary, in suspension test, the addition of myrosinase significantly increased mitotic gene conversion, probably due to the formation of GNST-derived phenylethyl isothiocyanate (PEITC) breakdown product. Taken together, our data suggest that GNST exerts a dual effect: while strongly inhibiting the microsomal (bioactivating) metabolism, GNST also possesses genotoxic activity. This concomitant mutagenic activity underlines the necessity of overall toxicological characterization of this (or any other molecule) prior to mass chemopreventive use.

Protective effect of lipoic acid against hydrogen peroxide in yeast cells.

Lipoic acid (LA) is found in all kinds of cells, it is widely used in medicine and as a dietary supplement, and it is involved in different physiological functions. Even if there are many papers regarding therapeutic effects of LA, medical research does not always support its effectiveness and little is known about LA metabolism in eukaryotic cells. In this work the probable protective effect of LA was investigated employing five strains of yeast Saccharomyces cerevisiae through short term assays. In particular LA behaviour in oxidative stress conditions was studied. For this purpose hydrogen peroxide was used as oxidant. In D7 strain, LA showed antimutagenic effects against hydrogen peroxide and decreased significantly cytochrome P450. To better elucidate the effect of LA the following yeast strains carrying deletions in superoxide dismutase genes (SOD) were employed: EG-103 (wild type), EG-110 strain (without mytochondrial SOD), EG-118 (without cytoplasmatic SOD) and EG-133 (without both enzymes). LA increased the number of mitotic divisions in EG-103, EG-110 and EG-133 and in growing cells (EG-103, EG-110, EG-118) it increased survival percentage with respect to hydrogen peroxide. The positive action was evident in D7 and in EG strains and it showed that LA can be protective and antimutagenic against oxidants in yeast cells, via its antioxidant activity.

Neonatal aortic arch thrombosis as a result of congenital cytomegalovirus infection.

Thrombotic disease is rare in neonates. The main risk factors at this age are perinatal asphyxia, maternal diabetes, sepsis, polycythemia, dehydration, a low cardiac output, and in primis the catheterization of central lines. Another important risk factor is inherited thrombophilia. Arterial thrombosis is even more rare than venous thrombosis and less related to most of the risk factors listed above; it occurs more frequently in the iliac, femoral, and cerebral arteries but very rarely in the aorta. Most of the described cases of aortic thrombosis are associated with the catheterization of an umbilical artery and involve the descending tract and the renal arteries; very few relate to the ascending tract and the aortic arch. The possible role of virus-induced primary vascular endothelium damage in the etiopathogenesis of neonatal arterial thrombosis has been previously hypothesized. Herpesviruses, particularly human cytomegalovirus (HCMV), can infect endothelial cells and directly damage intact vascular endothelium, altering its thromboresistant surface as a result of procoagulant activity mediated by specific viral surface phospholipids, necessary for the coagulation enzyme complex assembly that leads to thrombin generation. We describe a case of congenital aortic arch thrombosis. The clinical, laboratory, and virologic pictures; the anatomopathologic findings (fully compatible with viral infection); the detection of HCMV in various tissues (including the aorta); and the absence of other causes of aortic thrombosis make it possible to attribute the case to a severe congenital HCMV infection with multiple organ involvement, after the primary infection of the mother. The hemostatic system disorders and hemodynamic disturbances related to viral cardiac damage explain the clinical features of the case and indicate that congenital HCMV infection should be included among the causes of neonatal aortic thrombosis.

Neurocardiogenic syncope in selected pediatric patients--natural history during long-term follow-up and effect of prophylactic pharmacological therapy.

OBJECTIVE: The natural history of pediatric patients with severely symptomatic neurocardiogenic syncope is poorly defined respect to the likelihood of remission or symptomatic recurrence along time. We undertook this study to investigate the likelihood of clinical relapse, and to assess the effect of prophylactic pharmacological treatment in the most symptomatic patients. METHODS: Twenty-nine patients with neurocardiogenic syncope were studied at our Institution: 14 (12 +/- 3.6 years) highly symptomatic received prophylactic therapy with beta-blockers guided by head up tilt (HUT), whereas 15 (12.2 +/- 2.7 years) moderately symptomatic received only education to avoid triggering of the vasovagal reflex and to abort forthcoming syncope. Patients were then followed respectively for 33.7 +/- 9.0 and 33.3 +/- 8.7 months (p = NS). RESULTS: The average duration of symptoms before HUT was 9.0 +/- 4.3 months (range 3-17) for treated patients, and 6.2 +/- 2.5 months (range 2-11) for those untreated (p < 0.05). Treated patients had also a greater number of symptomatic events: 6 +/- 2 vs. 2 +/- 1 (p < 0.001). During follow up, 9/15 untreated and 6/14 treated patients had at least 1 recurrence, with an odds ratio of 2 (95% CI 0.72-5.49). Clinical events were greatly reduced in both groups at follow up, but treated patients had a significantly greater reduction either of syncopal (p < 0.001) or near syncopal events (p < 0.02). Time to the first recurrence, syncope or near syncope, was shorter for untreated vs treated patients: 5 +/- 2 vs. 25 +/- 12 months (p < 0.001). Looking at the time course of all clinical recurrences, 23/26 occurred in untreated patients, whereas 7/10 occurred in treated patients within 24 months. An attempt to therapy discontinuation was made after 30 months in 4 patients, and resulted in half of them being asymptomatic, and half with a single minor recurrence. CONCLUSIONS: Spontaneous reduction of symptoms occurs along time in pediatric patients with neurocardiogenic syncope, so that recurrences are very unlikely after 24 months from first diagnosis. Tiered prophylactic therapy may be guided by HUT in selected highly symptomatic patients; beta-blockers appear a very effective intervention. Larger, prospective controlled studies are required to investigate the role of any intervention in moderately symptomatic patients.

Protective effects of vitamins and selenium compounds in yeast.

Antimutagens and anticarcinogens are known to play an important role in decreasing damages induced by oxidants. In this study, we investigated the genotoxic and antimutagenic potential of two selenium compounds (sodium selenite: Na(2)SeO(3); seleno-DL-methionine: C(5)H(11)NO(2)Se) and Vitamins A and E in yeast cells of Saccharomyces cerevisiae. An oxidative mutagen (hydrogen peroxide (H(2)O(2)), HP) was chosen as positive control. We determined the enzymatic activities involved in the protection against oxidative damages (catalase: CAT; superoxide dismutase: SOD; glutathione peroxidase: GPx) in the cytosolic extract of yeast cells. The results demonstrated that selenium compounds exerted both mutagenic and antimutagenic effect at different concentrations. Antimutagenesis was evident both in stationary and in logarithmic phase cells. Catalase, SOD, and GPx were significantly increased in the presence of all the compounds assayed. Vitamins A (retinol) and E (alpha-tocopherol) did not have toxic or mutagenic action.

Mycotic aneurysm of the thoracic aorta presenting as pneumonia.

Mycotic aneurysms of the thoracic aorta rarely occur in children. We report an unusual case of a mycotic aneurysm of the descending aorta in a 4-year-old boy presenting with respiratory tract infection, which was rapidly complicated by atelectasis of the left lung. The patient's mycotic aortic aneurysm was diagnosed by contrast-enhanced spiral CT, whereas conventional chest radiographs did not detect its presence. An unsuspected mild aortic coarctation was also diagnosed at the time of admission. This case demonstrates that an aortic aneurysm may clinically and radiologically manifest itself with respiratory tract infection and atelectasis and that contrast-enhanced spiral CT is a fast and powerful tool for establishing the diagnosis.

Left superior vena cava persistence in patients undergoing pacemaker or cardioverter-defibrillator implantation: a 10-year experience.

OBJECTIVE: The persistence of a left superior vena cava (LSVC) has been observed in 0.3% of the general population as established by autopsy. In the adult population, it is an important anatomic finding if a left superior approach to the heart is considered. The aim of the study was to evaluate the prevalence of a LSVC in patients undergoing pacemaker (PM) and cardioverter-defibrillator (CD) implantation. DESIGN: We observed the prevalence of LSVC during a 10-year period; each patient undergoing PM or transvenous CD implantation received a left cephalic/left subclavian venous approach to the heart. With this technique, LSVC persistence is easily diagnosed during lead placement. RESULTS: A total of 1,139 patients consecutively underwent PM implantation during 10 years: 4 patients had persistent LSCV (0.34%). Among 115 patients undergoing CD implantation, 2 patients with LSVC (1.7%) were observed. Overall LSVC persistence was found in 6 of 1,254 patients (0.47%). Two patients, one of whom had no right superior vena cava (RSVC), received a left-sided PM, whereas two other patients received right-sided devices. Both CD patients received a left-sided active-can device: the first patient with a right-sided lead tunneled to the left pectoral pocket, as a result of poor catheter handling through the LSVC and coronary sinus, and the second patient with a screw-in lead from LSVC. Long-term follow-up of these patients (average +/- SD, 41 +/- 26 months) revealed absence of lead dislodgment and appropriate device function regardless of lead implantation site. CONCLUSIONS: Persistence of LSVC in adults undergoing PM/CD implantation is similar to that of the general population (0.47% in our study). The left-sided implant can be achieved by stylet shaping and by use of active fixation leads in most patients, with a reliable outcome at short term in addition to appropriate device performance at follow-up. Assessment of the RSVC is advisable when planning a right-sided implantation, since a minority of patients lacks this vessel.

Genotoxic and mono-oxygenase system effects of the fungicide maneb.

The in vivo effects of a commercial preparation of maneb on mono-oxygenase activities of hepatic microsomes of basal and induced rats were examined. In vitro experiments with the D7 strain of yeast Saccharomyces cerevisiae were also performed. In both basal and induced rats maneb caused a decrease in cytochrome P-450 content and aniline hydroxylase. Immunoblotting analysis using anti-P-450 IIE1 antibodies confirmed the data obtained for aniline hydroxylase activity. Maneb was toxic in cells of S. cerevisiae. On the basis of in vivo and in vitro experiments it can be concluded that maneb possesses a toxic activity attributable to its main metabolite ethylene thiourea. Immunoblotting analysis indicates that maneb biotransformation influences the IIEI P-450 isoform.

Evaluation of myocardial injury following repeated internal atrial shocks by monitoring serum cardiac troponin I levels.

INTRODUCTION: Electrical shocks delivered for atrial cardioversion (CV) may cause myocardial damage. The aim of this study was to assess the extent of myocardial injury caused by repeated intracardiac shocks delivered for low-energy internal atrial CV. METHODS AND RESULTS: Thirty-five patients with chronic persistent atrial fibrillation (AF) of different etiologies underwent CV with delivery of synchronized biphasic shocks (3.0/3.0 ms) between two catheters positioned in the right atrium and the coronary sinus. Shocks were delivered according to a step-up protocol (50 V, 180 V, then steps of 40 to 56 V up to 500 V, if necessary). In 23 patients, AF was reinduced after baseline CV, and CV was repeated. Myocardial injury was monitored by measuring cardiac troponin I (cTnI) serum concentrations in blood samples taken at baseline and at 2, 4, 8, 12, and 24 h after the procedure, by means of an immunoenzymologic assay (normal values, < or =0.6 ng/mL). A mean (+/- SD) of 6.9 +/- 3.4 shocks per patient were delivered (range, 2 to 17). Shocks delivered in each patient had a maximal energy of 7.3 +/- 4.0 J (range, 1.7 to 15.7). In 20 patients (57%), no evidence of myocardial injury (cTnI level, < or = 0.6 ng/mL) was found. In 13 patients (37%), mildly elevated cTnI levels (range, 0.7 to 1.4 ng/mL) in samples taken 4 to 12 h after CV suggested minor myocardial injury. In two patients (6%), higher cTnI levels were found in samples taken 4 to 8 h after CV (peak, 1.7 and 2.4 ng/mL), indicating a necrotic damage. Patients with no cTnI elevation, with mild cTnI elevation, or with cTnI levels >or =1.5 ng/mL did not differ significantly with respect to the total number of shocks delivered, the mean amount of energy delivered, and the cumulative amount of energy delivered. No clinical complications were observed. CONCLUSIONS: Following internal CV with the delivery of repeated shocks, minor elevations of cTnI serum levels could be detected in a significant proportion of patients, and this suggests subtle asymptomatic minor myocardial injury. The elevations of cTnI levels do not appear to be related to the number of shocks or to the amount of energy delivered.

Antimutagenesis studies of magnesium and calcium salts.

Magnesium is a microelement that is essential for biological functions and particularly for cellular metabolism. It has a central role in protein, lipid, carbohydrate, and nucleic acid synthesis, and it is important for muscular physiology and nerve excitability. Magnesium has an important role in the stability of biological membranes, it controls immune phenomena, and it activates over 300 enzymes. However, the mechanism of action of magnesium salts has not been well investigated and, in particular, its antimutagenesis properties and its effects in the detoxification of free radicals need further study. We investigated the effect of magnesium chloride, sulphate, carbonate, and oxide on the yeast Saccharomyces cerevisiae D7 strain, to evaluate their ability to protect against genotoxic damage. We found that magnesium salts induced antimutagenic effects in the cells harvested in the logarithmic phase by decreasing the induction of hydrogen peroxide. This, however, did not occur in the stationary phase. We also studied calcium salts of the type corresponding to those of magnesium and their protective role against the oxidative damage of free radicals and enzymatic activities, such as catalase, glutathione peroxidase, and superoxide dismutase, which are involved in antioxidative defenses.

Electrophysiological effects of flecainide and propafenone on atrial fibrillation cycle and relation with arrhythmia termination.

OBJECTIVES: (1) To investigate the electrophysiological effects of flecainide and propafenone during atrial fibrillation, and their relation to arrhythmia termination; (2) to investigate the effects of isoprenaline on atrial fibrillation in basal conditions and during treatment with class 1C drugs to evaluate the role of adrenergic stimulation on proarrhythmic events occurring during this treatment. DESIGN: Prospective, single centre study. SETTING: University hospital. METHODS: 10 patients with lone paroxysmal atrial fibrillation underwent an electrophysiological study. The dynamic behaviour of MFF (the mean of 100 consecutive atrial fibrillation intervals) was evaluated at two atrial sites after induction of atrial fibrillation either at baseline or after class 1C drug administration (flecainide or propafenone 2 mg/kg). The effects of isoprenaline on MFF and RR interval were also investigated both under basal conditions and during class 1C drug treatment. RESULTS: After induction of atrial fibrillation, mean (SD) MFF shortened with time, and was further shortened by isoprenaline infusion (177 (22) v 162 (16) v 144 (11) ms, p < 0.05). The administration of class 1C drugs reversed this trend and significantly increased the MFF to an average of 295 (49) ms, leading to conversion to sinus rhythm within 10 minutes in all patients. Atrial fibrillation was then reinduced on class 1C drugs: isoprenaline shortened the MFF and RR interval with a trend to AV synchronisation (223 (43) v 269 (49) ms for the MFF, 347 (55) v 509 (92) ms for the RR, p < 0.05); 1:1 sustained AV conduction occurred in two patients, at 187 and 222 beats/min respectively. One of these patients underwent electrical cardioversion because of haemodynamic collapse. CONCLUSIONS: Class 1C drugs are effective at restoring sinus rhythm by increasing the MFF to a much greater extent than observed in self terminating atrial fibrillation episodes, and reversing the spontaneous atrial fibrillation behaviour (progressive shortening of MFF and self perpetuation of atrial fibrillation). MFF prolongation with 1:1 conduction at fast ventricular rates may lead to synchronisation during adrenergic stimulation, with a very short ventricular cycle; hence it is advisable to keep the patients at rest after acute class 1C drug loading or to consider pharmacological modulation of AV conduction for patients who are prone to a fast ventricular response.

Favorable effects of flecainide in transvenous internal cardioversion of atrial fibrillation.

OBJECTIVES: The aim of the study was to evaluate the effects of intravenous (IV) flecainide on defibrillation energy requirements in patients treated with low-energy internal atrial cardioversion. BACKGROUND: Internal cardioversion of atrial fibrillation is becoming a more widely accepted therapy for acute episode termination and for implantable atrial defibrillators. METHODS: Twenty-four patients with atrial fibrillation (19 persistent, 5 paroxysmal) underwent elective transvenous cardioversion according to a step-up protocol. After successful conversion in a drug-free state, atrial fibrillation was induced by atrial pacing; IV flecainide (2 mg/kg) was administered and a second threshold was determined. In patients in whom cardioversion in a drug-free state failed notwithstanding a 400- to 550-V shock, a threshold determination was attempted after flecainide. RESULTS: Chronic persistent atrial fibrillation was converted in 13/19 (68%) patients at baseline and in 16/19 (84%) patients after flecainide. Paroxysmal atrial fibrillation was successfully cardioverted in all the patients. A favorable effect of flecainide was observed either in chronic persistent atrial fibrillation (13 patients) or in paroxysmal atrial fibrillation (5 patients) with significant reductions in energy requirements for effective defibrillation (persistent atrial fibrillation: 4.42+/-1.37 to 3.50+/-1.51 J, p < 0.005; paroxysmal atrial fibrillation: 1.68+/-0.29 to 0.84+/-0.26 J, p < 0.01). In 14 patients not requiring sedation, the favorable effects of flecainide on defibrillation threshold resulted in a significant reduction in the scores of shock-induced discomfort (3.71+/-0.83 vs. 4.29+/-0.61, p < 0.005). No ventricular proarrhythmia was observed for any shock. CONCLUSIONS: Intravenous flecainide reduces atrial defibrillation threshold in patients treated with low-energy internal atrial cardioversion. This reduction in threshold results in lower shock-induced discomfort. Additionally, flecainide may increase the procedure success rate in patients with chronic persistent atrial fibrillation.

Isolation of a novel metabolizing system enriched in phase-II enzymes for short-term genotoxicity bioassays.

Murine S9 liver fractions isolated from mice fed 7.5 g kg-1 2(3)-tert-Butyl-4-hydroxyanisole (BHA) for 3 weeks were tested to determine: (a) the profile of both phase-I and phase-II xenobiotic metabolizing enzymes; (b) their ability to induce in vitro covalent binding of some precarcinogens to calf thymus DNA; and (c) their activation in a standard genetic toxicology assay. With regard to phase-I pathway, the S9 fraction expressed various cytochrome P-450-(CYP) (classes 1A1, 1A2, 2B1, 2E1, and 3A)-dependent biotransformation enzymes at levels comparable with those present in murine control liver. For post-oxidative enzymes, the S9 expressed high levels of glutathione S-transferases (up to 12-fold increase), glutathione S-epoxide-transferase (up to 2.6-fold), UDP-glucuronosyl transferase (up to 5.3-fold) and epoxide hydrolase (up to 2.6-fold) activities, as compared to untreated mice. The in vitro DNA binding of the precarcinogenic agents [14C]-1,4-dichlorobenzene, [14C]-1,2-dichlorobenzene and [14C]-1,4-dibromobenzene, mediated by BHA-induced cytosol and/or microsomal preparation, showed an increase in specific activity comparable to that observed with phase-I (PB/beta NF) induced S9. In some instances, covalent binding was even more elevated using the BHA-induced systems as compared with traditional S9 fractions. For example, cytosol derived from BHA-administered mice was able to induce a significant binding to calf thymus DNA up to 26.2-fold increase for [14C]-1,4-dichlorobenzene, while cytosol from PB/beta NF was not. A high mutagenic response on diploid D7 strain of Saccharomyces cerevisiae as exemplified by a marked induction of mitotic gene conversion and point (reverse) mutation confirmed that BHA-derived S9 fractions activate precarcinogens to final genotoxins. Because a number of chemicals are activated by either oxidative or post-oxidative enzymes, the use of metabolizing biosystems, with an enhanced phase-II pathway, together with classical S9 fractions, can improve the sensitivity of the assay in detecting unknown genotoxins.

Efficacy and tolerability in fully conscious patients of transvenous low-energy internal atrial cardioversion for atrial fibrillation.

Transvenous low-energy atrial cardioversion was performed in a series of fully conscious patients (30 patients with chronic atrial fibrillation and 5 patients with paroxysmal atrial fibrillation). The results show that internal atrial defibrillation is effective and tolerable in most patients.

Malignant vasovagal syncope: a randomised trial of metoprolol and clonidine.

OBJECTIVE: To evaluate the efficacy of head up tilt guided treatment with metoprolol and clonidine in preventing the recurrence of syncope in patients with malignant vasovagal syncope. PATIENTS: 20 patients (9 men and 11 women, mean age 33 (SD 17), range 14 to 62 years) with severe symptoms. DESIGN: Randomised double blind crossover trial; efficacy was assessed by head up tilt testing. RESULTS: Metoprolol was more effective than clonidine in abolishing syncope (19/20 v 1/20, P < 0.001) but clonidine showed some beneficial effects on time to syncope and severity of hypotension in 12 patients. During an average follow up of 15 (3) months there was a significant reduction in the recurrence of symptoms compared with the previous year in patients who had tilt up guided treatment (18 metoprolol, 1 clonidine). CONCLUSIONS: Treatment guided by head up tilting is a reliable method of treating patients with malignant vasovagal syndrome. Metoprolol was an effective long term treatment for preventing syncope. High doses were more effective and a careful dose titration period helped to minimise withdrawal symptoms and side effects.

Mutagenicity and chemical analysis of airborne particulate matter collected in Pisa.

The genotoxic effects of airborne particulate samples collected from two urban areas during various traffic intensity levels were evaluated using the yeast Saccharomyces cerevisiae (D7 strain) and Salmonella typhimurium (TA98 and TA100 strains). Standard protocols were used, in compliance with recent legislation. Airborne particulate data reveal that genotoxic effects were more evident in the samples collected in the area with intense moving traffic than in the area with limited traffic. Particulate, benzene, toluene, NO2, CO, and heavy metal determinations in these two areas show that their concentrations are related to the intensity of traffic.