Perturbation of murine liver cyp-superfamily of isoforms by different combinations of pesticide mixtures.

It was previously found that fenarimol, vinclozolin or acephate, three of the most used pesticides worldwide, provoked a marked perturbation of murine cytochrome P450 (CYP)-linked monooxygenases. Here, to more closely mimic human exposure, it was investigated whether different pesticide combinations administered i.p. in male Swiss Albino CD1 mice in single or repeated fashion (daily, for three consecutive days), affect CYP-dependent oxidations. The four simulated mixtures showed a complex pattern of CYP induction and suppression, especially after repeated injection. For example, while fenarimol alone was the most inducing agent--reaching a 79-fold increase over control in testosterone 2alpha-hydroxylase--followed by vinclozolin and acephate, coadministration with the former markedly reduced induction. Coadministration with vinclozolin, determined various positive and negative modulations. An increase of CYP2B1/2 and CYP3A1/2-associated oxidases and a decrease of ethoxycoumarin metabolism was observed in the acephate and vinclozolin mixture. An equivalent or reduced CYP expression, if compared to double combinations, was seen using the complete mixture. Taken as a whole, the unpredictability of the recorded effects with simple mixtures, shrinks the misleading extrapolation performed on a single pesticide. If reproduced in human, such changes, altering either endogenous metabolism or biotransformation of ubiquitous toxins, might have public health implications.

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.

Cardiac involvement in Churg-Strauss syndrome: a follow-up of three cases.

Three cases of Churg-Strauss syndrome with myocardial involvement are reported. Cardiac disease is known to be the major cause of death in Churg-Strauss syndrome. Aggressive therapy (steroids and cyclophosphamide) may cure the myocardial dysfunction associated with the disease.

Electrophysiological evaluation of the sinus node in patients with atrioventricular and/or intraventricular conduction defects.

The authors evaluated retrospectively sinoatrial conduction time (SACT), sinus node recovery time (SNRT), and corrected sinus node recovery time (CSNRT) in 272 patients with atrioventricular and/or intraventricular conduction defects without evidence of overt sinus node dysfunction. The study was designed to determine the prevalence of electrophysiologic sinus node abnormalities in patients with overt atrioventricular and/or intraventricular conduction defects. One or more sinus node electrophysiological abnormalities were observed in 133 cases (48.9%). There was a significant prevalence of electrophysiologic sinus node abnormalities only in patients older than 71 years of age. The data suggest that the involvement of the specialized conduction system is much more diffuse than one might expect simply observing the single recorded ECG defect and that the prevalence of associated defects of the conduction system increases with increasing age of patients.

Phrenic nerve paralysis following pediatric cardiac surgery. Role of diaphragmatic plication.

Eighteen children sustained unilateral phrenic nerve paralysis (PNP) after cardiac surgical procedures. Ten (Group I), under 7 months (mean: 2.9 +/- 2.2), required long-term ventilatory assistance (mean: 23.9 +/- 13.0 days); they failed to be weaned from the ventilator. All underwent diaphragmatic plication (DP). DP was performed late in 7 cases (Group Ia) with a mean time of 30.8 days between surgery and DP, and early in 3 others (Group Ib) with a mean time of 10.2 days. Eight children (Group II), older than 1 year, tolerated PNP better and could be extubated early without diaphragmatic plication. In Group Ia severe lung infections were recorded in 5 before or/and after DP, and two died at 3 and 30 days after plication. Five children from Group Ia and all 3 from Group Ib were late survivors. They could be weaned from ventilatory support in a mean time of 3 days after DP, although those with severe lung infection (Group Ia) took the longest time. All from Group II were late survivors. We conclude: PNP is well tolerated without plication in children older than 1 year. However early DP offers excellent and immediate results in infants with PNP. Early DP in these children avoids or reduces severe lung infections and death.

Pre-operative sinus node function in adult patients with atrial septal defect (ostium secundum type).

The authors studied, pre-operatively, the sinus node function in adult patients with secundum atrial septal defect and large left-right shunts, using Holter ECG and electrophysiological tests. Sinus node electrophysiological tests were found abnormal in 17 out of 26 patients; on the contrary, Holter monitoring was always within normal limits. The authors believe that concealed sinus node dysfunction existing before surgical correction may be a cause of early, acute, and reversible, post-operative sick sinus syndrome.

Value of purinic compounds in assessing sinus node dysfunction in man: a new diagnostic method.

The purpose of this paper is to investigate whether the inhibitory action of purinic compounds (striadyne: STR) on the sinus node is quantitatively different on a pathological sinus node in comparison to a normal one and thus whether it is possible, as suggested by other authors, to use STR as a pharmacological test in the diagnosis of sick sinus syndrome (SSS). With this aim we investigated 55 patients, divided into 3 groups according to ECG and sinus function evaluation tests: 1--normal; 2--SSS (2a: flagrant SSS; 2b: latent SSS); 3--excess vagotonia and/or abnormal response to vagal stimulation. In all patients after a prophylactic insertion of a temporary pacemaker, 30 mg of STR were rapidly injected i.v. and the surface and intracavitary ECG continuously recorded until the basal state was regained; the following parameters were evaluated: average baseline sinus cycle (SC), minimum and maximum SC after the drug. In all patients STR caused first a slowing, then an acceleration of the sinus rate. SC lengthening was moderate in groups 1 and 3 [max SC was respectively 740-1820 ms (1198 +/- 290.9 ms) and 720-1440 ms (1157.5 +/- 223.3 ms)], but it was severe in patients with SSS [max SC in group 2a 2500-11880 ms (5398.3 +/- 2687.4 ms) in group 2b 1620-11140 ms. (4470.7 +/- 3660.6 ms)]. The difference between the max post STR SC of SSS patients, and the control group was highly significant P less than 0.001). Assuming as upper limit of the normal a value of 2071 ms. (corresponding to the mean + 3 standard deviations of the response of the control group) we recorded abnormal responses in 100% in group 2a and in 85.7% in group 2b, whereas there were no abnormal responses in group 3. In addition, nodal atrioventricular block occurred frequently. The authors believe this test could be useful in the diagnosis of SSS, but it is essential to insert a ventricular pacing catheter prophylactically if this test is used.

[Reproducibility of electrophysiological tests of sinus node function in patients with sick sinus syndrome. Reproducibility of tests of sinus node recuperation time, corrected sinus node recuperation time and sino-atrial conduction time]. / Riproducibilità dei tests elettrofisiologici di funzionalità sinusale in pazienti con sick sinus syndrome. Riproducibilità del TRNS, del TRNSC e del TCSA.

In order to clarify whether SNRT, CSNRT and SACT are reproducible tests, 20 patients with sick sinus syndrome underwent two successive electrophysiological studies with an interval of 24 hours; mean sinus cycle, SACT, SNRT, CSRNT were evaluated. Although no significant differences were found between the mean values of the two studies, in isolated cases remarkable variations of one or more parameters were observed. We conclude that SNRT, CSNRT and SACT are reproducible tests only if mean values in a large number of patients are considered, while they are not as useful in quantifying sinus node dysfunction in single cases. In conclusion, while SNRT, CSNRT and SACT are reproducible and useful in comparing data from relatively large number of patients, great caution should be used before drawing conclusions of potentially serious diagnostic and prognostic consequence in the single patient.