Involvement of Jun and Rel proteins in up-regulation of interleukin-4 gene activity by the T cell accessory molecule CD28.

CD28 serves as a costimulatory cell surface molecule in T cell activation. CD28 signaling may also play a role in balancing the inflammatory/humoral (Th1/Th2) responses during an immune reaction. CD28 costimulation has been shown to promote the production of Th2 cytokines including interleukin (IL)-4, a key cytokine essential for Th2 differentiation and for the pathogenesis of allergic inflammation. In this study, we show that IL-4 mRNA and activity of the IL-4 promoter can be activated by the CD28 signal alone and are further augmented by CD28 costimulation of alpha-CD3- or mitogen-activated Jurkat T cells. Two important IL-4 enhancer elements, positive regulatory element (PRE)-I and P1, are found to respond to CD28 stimulation-induced transactivation. In contrast to the Th1 IL-2 CD28RE, activity of the IL-4 PRE-I and P1 can be induced by the CD28 signal alone. In correlation with CD28-induced transcriptional activation, AP-1 (c-Jun, JunD) and NF-kappaB/Rel (c-Rel, RelA) family members are found to bind to the two regulatory elements PRE-I and P1 upon CD28 stimulation. The data provide the first mapping of the CD28-responsive site in a Th2 cytokine gene, the IL-4 gene. They also show that the CD28 signal can directly activate a gene (e.g. IL-4) at the transcriptional level.

[Prognostic value of the exertion test in patients treated with thrombolytic therapy for acute myocardial infarct]. / Il valore prognostico del test da sforzo in pazienti trombolisati per infarto acuto del miocardio.

Prognostic value of exercise testing after thrombolytic therapy in patients with acute myocardial infarction. Few studies have evaluated the prognostic value of exercise testing in patients suffering from acute myocardial infarction (AMI) and thrombolysis. For this reason the authors studies 398 patients divided into two groups: 189 thrombolysed patients (T) and 209 non-thrombolysed patients (NT), matched for age, sex, AMI site and treatment received. Thrombolysis was performed within 6 hours of the onset of symptoms using rt-PA in an accelerated regime (90 degrees) preceded by sodium heparin infusion 5000 UI i.v. in bolus, and followed by sodium heparin for 5 days, maintaining a PTT value 2-3 times the basal level. The efficacy of thrombolytic treatment was confirmed by the presence pf at least two of the following markers: CK peak time, rapid reduction of ST overunlevelling, reperfusion arrhythmia. All patients underwent exercise testing using the cycloergometer after suspending treatment at 3 weeks and 6 months after AMI, and a echocardiographic examination on the first day and after 6 months. These data show that thrombolytic treatment reduces the myocardial damage during the course of AMI, enabling the patient to exercise longer and causes improved myocardial contractility with a lower asynergic index compared to non-reperfused patients. Moreover, significantly fewer ergometric tests that were positive for residual ischemia were observed in T compared to NT. The incidence of mortality one year after AMI was low in both groups, albeit lower in T. This confirms the important prognostic role of ergometric tests also in this population.

Correlation between late potentials duration and QTc dispersion: Is there a causal relationship?

QTc interval dispersion (QTcd) analysis (difference between maximum and minimum QTc calculated from at least five of the standard 12 ECG leads) and signal-averaged electrocardiograms were performed on 23 patients referred to our coronary care unit because of acute myocardial infarction. Late potentials were considered positive if all three of the following criteria were satisfied: (1) total QRS duration (QRSd) > 114 ms; (2) duration of QRS under 40 muV (LAS 40) > 38 ms; (3) root mean square voltage of the last 40 ms of QRS (RMS 40) < 25 muV. Patients were divided into two groups according to the presence (group A, 9 patients) or absence of late potentials (group B, 14 patients). Group A patients showed a significantly higher QTcd (0.0652 +/- 0.0177 s vs. 0.0448 +/- 0.0201 s; P = 0.021) and a significantly longer mean QTcm (0.43117 +/- 0.01817 s vs. 0.40472 +/- 0.03013 s; P = 0.028) than group B patients. Among the three different parameters used to define the presence of late potentials, QTcd was significantly related to LAS 40 (r = 0.418, P = 0.047) and mean QT cm to QRSd (r = 0.497; P = 0.016). We also found a significant correlation between QTcd and mean QTcm (r = 0.426; P = 0.043). In conclusion, our data suggest that (1) the presence of late potentials is associated with a greater dishomogeneity of ventricular recovery time; (2) the longer the duration of late potentials, expressed by LAS 40, the greater the QTcd, suggesting that the dispersion of repolarization could be attributed to slowly conducting areas from which late potentials arise; (3) mean QTcm is not useful to identify these areas because it is more affected by total rather than by terminal QRS duration; (4) regional discrepancies of ventricular recovery time are connected with general repolarization duration.

Morpho-functional assessment of interatrial septum: a transesophageal echocardiographic study.

BACKGROUND: Despite the increasing number of reports on lipomatous hypertrophy of interatrial septum, a standardization of measurement of the dimensions of the interatrial septum (IAS) in the different phases of cardiac cycle has not been reported. Moreover, no data on modification of thickness with age and in specific cardiac diseases are available. OBJECTIVE: Our purpose was to study whether the changes of thickness and thinning of IAS may be related to age, left atrial dimension, cardiac cycle and different cardiac diseases. METHODS: 248 patients (mean age 52.7 +/- 19.9 years) underwent transthoracic (TTE) and transesophageal (TEE) echocardiography. IAS was measured at the constant regions anterior and posterior to the fossa ovalis. IAS thickness (tk), thinning (th) and % thinning (% th) were measured. RESULTS: IAS thickness ranged from 4 to 13 mm at the time of ventricular end-systolic phase (mean 6.7 +/- 1.9 mm) and from 6 to 16 mm at the time of atrial systole (mean 9.9 +/- 1.8 mm); significant statistical difference between these values was found (P < 0.01). IAS thinning ranged from 1 to 7 mm (mean 3.42 +/- 1.8) while % IAS thinning from 18 to 76% (mean 36.53 +/- 16.36%). Statistical analysis showed a significant positive correlation between age and ventricular end-systolic thickness and atrial systolic thickness and thinning. An insignificant correlation was found between age and % IAS thinning and between left atrial dimension and IAS tk and th. CONCLUSIONS: Our results demonstrate that IAS thickness increases by age; no correlation exists between IAS thinning and age. There is no difference between IAS thickness and thinning in patients with or without cardiac disease. We believe that the thickness of IAS can be considered hypertrophic only if it exceeds the value of 15 mm during both ventricular end-systolic and atrial systolic phases of the cardiac cycle. IAS thickness and thinning might be an additional parameter to evaluate systolic atrial function particularly with regard to maintenance of synus rhythm after conversion from atrial fibrillation as well as to better understand its role in determining the filling of ventricles in different clinical conditions.

[The therapeutic prospects of ischemic cardiopathy]. / Prospettive terapeutiche della cardiopatia ischemica.

Having thoroughly reviewed the risk factors and pathophysiologic features of ischemic heart disease, the authors describe therapeutic protocols at present in use and take stock of the perspectives opened by new drugs with different kinetic and dynamic and more advanced properties compared to those at present in use.

Propafenone in Wolff-Parkinson-White syndrome at risk.

We present our experience on the efficacy of propafenone in ten symptomatic patients with Wolff-Parkinson-White syndrome. The symptoms were dizziness in seven patients and syncope in three patients. While experiencing the symptoms, three of them presented an episode of atrial fibrillation, the shortest preexcited RR intervals being 140, 190, and 200 ms. In the other seven patients, the ECG was not recorded during the symptoms, but an episode of atrial fibrillation was subsequently induced by transesophageal pacing. The shortest preexcited RR intervals during induced atrial fibrillation were 180, 200, 270, 240, 230, 250, and 200 ms. Seven patients had both atrial fibrillation and supraventricular tachycardia. Propafenone (1-2 mg/kg) administered IV in only the patients with sustained atrial fibrillation (spontaneous in two and induced in one patient) prolonged the shortest preexcited RR intervals from 190, 200, and 180 ms to 340, 335, and 340 ms. In the other seven patients, propafenone was not given IV because atrial fibrillation rapidly deteriorated into ventricular fibrillation (one patient) or spontaneously reverted within 1-2 minutes to sinus rhythm (six patients). After oral propafenone, serial trans-esophageal pacing studies reinduced atrial fibrillation in 4 of 6 patients (the shortest preexcited RR intervals increased from 190, 180, 200, and 270 ms to 420, 320, 340, and 380 ms); only in one patient was it possible after propafenone to induce an atrial flutter without preexcitation. After propafenone therapy in 4 of 7 patients, supraventricular tachycardia was not inducible.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible adverse effects on the cardiovascular system of an antiarrhythmic drug mexiletine.

Mexiletine (MXT) is a drug endowed with a marked antiarrhythmic activity which may be included in 1B class of drugs employed in the therapy of arrhythmias. In experimental cardiovascular research, MXT at very high doses induces a decrease in the arterial blood pressure and cardiac performance of dogs. MXT reduces the carotid baroreceptor responses, the fall in blood pressure following pharadic stimulation of the peripheral trunk of the vagus nerve and it also inhibits catecholamine uptake. All these effects may be related to the local anaesthetic activity which MXT possesses and which need careful consideration in the clinical use of the drug.

N-monosubstituted urethanes and esters of 6-cis-dimethylamino-1,3,3-trimethyl-2-oxabicyclo-[2.2.2]octan-5-trans-ol with hypotensive and other activities.

The synthesis of 6-cis-dimethylamino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-trans-ol (III) starting from 1,3,3-trimethyl-6-nitrimino-2-oxabicyclo[2.2.2]octane is described. Starting from aminoalcohol (III), a series of N-substituted urethanes (IV) and esters (V), as well as the rigid analogue of acetylcholine (VII), were prepared. A number of compounds (V) and particularly (IV) showed remarkable hypotensive and bradycardic activities in rats, whereas the p-aminobenzoate (V h) showed infiltration anesthesia in mice comparable to that of lidocaine. Antiarrhythmic activity in mice and antiacetylcholine activity in vitro are also reported.

[Sodium phosphocreatine and the cardiovascular and respiratory systems]. / Fosfocreatina sodica ed apparato cardiovascolare e respiratorio.

In the dog, rat and chick, phosphocreatine-Na has not caused, from an experimental point of view, significative modifications of the cardiovascular- and respiratory-apparatus, of the reactivity of the cardio-regulator centers, of the baroreceptorial carotid-sinus and glomus reactivity, of the gangliar-, muscarinic-, histaminergic-, dopaminergic-, beta-adrenergic- and serotoninergic- vasomotor reactivity; only the vasomotor reactivity of a constrictive-type induced by epinephrine, nor-epinephrine, occlusion of the two common carotid arteries, hypertension and by BaCl2 is moderately reduced. It is interesting to note that the hypotensive response evoked by adenosine was augmented.

Ester of 6-cis-dialkylamino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-trans-ol with hypotensive and other activities.

Three series of esters of 6-cis-dialkylamino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-trans-ol (dialkylamino = pyrrolidino, piperidino, morpholino) are described. A number of these compounds showed strong hypotensive activity in rats, as well as infiltration anesthesia and antiarrhythmic activity in mice. The lowering effects on heart rate in rats are also described.

Derivatives of 1,2,3,3-tetramethyl-2-azabicyclo[2,2,2]octan-5-trans-ol with antiarrhythmic and other activities. V.

A series of N,N-dialkyl 5-trans-carbamoyloxy-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octanes was prepared by reaction of 1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octan-5-trans-ol with phosgene, followed by aminolysis of the resulting chlorocarbonate with aliphatic secondary amines. 5-Chloro-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2] octane (cis/trans mixture) was isolated as by-product of the reaction. A number of urethanes showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.