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This study was prompted by previous findings that prenatal ethanol exposure may interfere with the differentiation of the sexual behavior in rats. Ethanol (6 g/kg) administered daily from day 15 postconception, resulted in elevated testosterone (T) levels on Day 18 in male and female fetuses. No alterations of sexual behavior in the ethanol-treated male offspring were seen under these conditions. However, in ethanol-treated female offspring the onset of regular estrous cycling was significantly delayed. Acute treatment with doses of ethanol, 2, 4 or 6 g/kg, was ineffective in influencing plasma T levels of the fetuses. Acute treatment with 3 g/kg ethanol did not prevent the rise of T levels normally occurring immediately after birth. In adulthood, but not at prepubertal age (Day 30), treatment of male rats with 2 g/kg ethanol caused a depression of plasma T levels. Possible mechanisms affected by ethanol exposure and influencing on the fetal development were discussed.

The plasma or serum concentrations of testosterone, LH, FSH, PRL, cortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, estrone and estradiol were monitored in 8 healthy male volunteers for a period of 48 hr after administration of one large dose of ethanol (1.75 g/kg BW) within the first 3 hr of the experiment. Each subject served as his own control in an identical experiment without ethanol. Blood alcohol concentration reached a maximum of 1.51 +/- 0.08 g/l (mean +/- SEM) 4 hr after the start of drinking. The maximum decrease in serum testosterone was observed at 12 hr when the serum concentrations of gonadotropins were still unchanged. The decrease in serum testosterone persisted at 24 hr despite increases in the serum levels of LH and FSH. The serum or plasma concentrations of PRL, cortisol, 17-hydroxyprogesterone, androstenedione and dehydroepiandrosterone were clearly increased 4 hr after the start of drinking. The increase in serum cortisol lasted as long as the decrease in serum testosterone. No significant changes were found in plasma concentrations of estrone and estradiol. Our results suggest that in addition to direct testicular effects of alcohol, increased adrenal secretion of cortisol may contribute to the decrease in serum testosterone in men acutely intoxicated with ethanol.

Non-invasive estimation of the mean pulmonary capillary wedge pressure was accomplished by simultaneous electrocardiographic, phonocardiographic and continuous wave Doppler echocardiographic recordings. The interval from the onset of the QRS complex to the Doppler determined mitral valve closure (Q-MC) and the interval from the phonocardiographic aortic component of the second heart sound to the Doppler determined mitral valve opening (A2-MO) were measured. The non-invasive registrations were carried out simultaneously with direct measurements of the wedge pressure. In an initial group of 22 patients, a significant correlation was observed between the intervals alone and the wedge pressure, r = 0.60, SEE = +/- 6.9 mmHg, p less than 0.01, for the Q-MC interval and r = -0.70, SEE = 6.2 mmHg, p less than 0.001 for the A2-MO interval. A closer correlation was observed between the ratio Q-MC/A2-MO and the measured wedge pressure, r = 0.93, SEE = +/- 3.1 mmHg, p less than 0.001. The linear regression equation, PCW = 19.5 (Q-MC/A2-MO) + 3.0 (mmHg), was applied prospectively to a second group of 23 patients. Again the relationship between estimated and measured wedge pressure was highly significant, r = 0.90, SEE = +/- 3.1 mmHg, p less than 0.001. Twenty-two patients were also studied during an exercise test, and acceptable non-invasive recordings were obtained in 19 of them. The change in estimated wedge pressure during activity related closely to the change in actual wedge pressure, r = 0.80, SEE = +/- 5.7 mmHg, p less than 0.001. A simplified equation suitable for routine clinical practice, PCW = 24 (Q-MC/A2-MO) (mmHg), yielded almost equally accurate estimates of the wedge pressure over a wide range of pressures. The simplicity and reasonable accuracy of Doppler-assisted estimation of the wedge pressure makes it useful in the evaluation and follow-up of patients with suspected cardiac disorders. The method may assist in evaluating the effects of diagnostic or therapeutic procedures, since it is sufficiently sensitive to detect acute directional changes in wedge pressure.

Estimation of the orifice area is of major importance in the timing of valve dilation or surgery in patients with mitral stenosis. Determination of the area has traditionally been accomplished at cardiac catheterization by the Gorlin equation. The valve area can also be estimated noninvasively with Doppler echocardiographic measurements of the pressure half-time, which is inversely proportional to the area. This method has gained widespread acceptance, but its accuracy has recently been questioned and factors other than reduction of orifice area appear to modify the pressure half-time. In the present study, the influence of left ventricular stiffness (defined as diastolic pressure rise per milliliter of mitral flow) and peak atrioventricular pressure difference on the pressure half-time was examined both in a hydraulic model and by review of data from 35 patients with mitral stenosis. Left ventricular stiffness 100% in seven patients with coronary heart disease or aortic valve disease (or both), of whom all had a stiffness >0.2 mm Hg/ml.In conclusion, the pressure half-time is shortened and the valve area thus overestimated if left ventricular stiffness is increased, which is often the case in patients with mitral stenosis associated with coronary heart disease or aortic valve disease.

In situ freeze clamping of livers using either pentobarbital anaesthesia (40 mg/kg) or cervical dislocation as means of sacrificing rats were compared in regard to the determination of the hepatic acetaldehyde (AcH) concentration following ethanol exposure. It was demonstrated that following cervical dislocation, the AcH concentration decreased by 50%, ethanol decreased by 7%, and the mitochondrial redox state, expressed by the 3-hydroxybutyrate/ acetoacetate ratio, increased by 100% within 40 s. The extrapolated 0-time values for AcH, ethanol concentration, and 3-hydroxybutyrate/ acetoacetate ratio were equal to values obtained from pentobarbital anaesthetized rats. AcH concentrations (5 to 100 μM) were also measured 60 minutes after administration of increasing doses of ethanol. A positive correlation between the hepatic AcH and ethanol concentration was found up to ethanol concentrations of about 20 mM, suggesting either an increase in ethanol oxidation, a decrease in AcH oxidation, or both were present concomitant with increasing ethanol concentrations. When ethanol concentrations were above 20 mM, a negative correlation between AcH level and ethanol concentration was observed, suggesting a decrease in ethanol oxidation, an increase in AcH oxidation, or both were occurring.

The influence of long-term lithium treatment on the ECG was investigated in 53 consecutive patients. An ECG was recorded prior to and 4 and 12 months after institution of lithium therapy. The most frequently observed change during treatment was flattening or inversion of the T wave. Heart rate decreased and P-Q interval increased slightly during therapy. There was no change in the S-T segment or the Q-T interval corrected for heart rate. Our data indicate that well monitored lithium treatment of patients with serum lithium concentrations of about 0.6 mmol/l does not cause serious ECG abnormalities. In the absence of symptoms or signs of heart disease, routine monitoring of ECG is not necessary during lithium treatment.

The mean pressure difference across the valve in aortic stenosis is an indicator of the severity of the obstruction to flow. Non-invasive determination of the mean pressure gradient by Doppler ultrasonography is, however, complicated by the squared relation between instantaneous velocities and pressure differences. The validity of a new simple formula for calculation of the mean pressure difference from the peak pressure difference was evaluated in 26 patients with aortic stenosis. The formula is: delta pmean = 0.64 delta ppeak, where delta pmean is the mean pressure gradient and delta ppeak the peak pressure gradient. There was a close correlation between the mean pressure differences determined by application of the formula to the peak pressure differences measured at catheterisation and the mean pressure differences obtained by planimetry (r = 0.97, SEE = 4.7 mm Hg). The correlation between mean pressure differences determined by continuous wave Doppler ultrasound and the formula and those measured by planimetry was also close (r = 0.91, SEE = 7.6 mm Hg) and only three patients showed a difference between the two methods of greater than 10 mm Hg. The new formula is a simple and reliable means of estimating the mean pressure difference from Doppler recordings and it facilitates the comparison of Doppler and catheterisation data.

The pathogenesis of disturbances of the initiation and conduction of the cardiac impulse in cardiac amyloidosis has been a matter of controversy. In this study, we have analyzed the histopathology of the sinoatrial node and the atrial myocardium in nine cases of familial amyloidosis with polyneuropathy. Our results indicate that in this disease, amyloid infiltration of the sinoatrial node and the atrial musculature per se may account for the electrophysiological disturbances of these regions.

To assess the severity of outflow obstruction in patients with aortic valve disease, the aortic valvar area was noninvasively determined in 22 patients with isolated aortic stenosis or combined stenosis and regurgitation. The ejection time (ET), maximal velocity ( V max ), and systolic velocity integral (SVI) of the aortic flow was obtained by continuous wave Doppler ultrasound. Left ventricular stroke volume (SV) was determined by radionuclide angiography, using a counts-based nongeometric technique with individual attenuation correction. Aortic valve area (AVA) was calculated using a modified Gorlin formula; AVA=SV(71.2 × ET × Vmax), and also by dividing the stroke volume by the systolic velocity integral; AVA=SVSVI. The two noninvasive determinations correlated closely with the valve areas obtained by invasive measurements; r = 0.95, SEE=±0.13 cm 2 by the modified Gorlin formula, and r = 0.94, SEE=±0.14 cm 2 by the integration method. The two noninvasive calculations showed almost uniform results; r = 0.98, SEE=±0.09 cm 2 . In conclusion, aortic valve area can be determined with reasonable accuracy by combining Doppler echocardiography and radionuclide angiography. This noninvasive approach may reduce the need for invasive measurements in patients with suspected aortic valve disease. In addition, radionuclide angiography provides important information about left ventricular function.

Diminished response of animals to ethanol after repeated exposure may be not only the result of adaptive changes at the site of ethanol action, but also the result of changes in the ethanol metabolism. The latter case, that is, metabolic tolerance, includes three major factors which may undergo adaptive changes: (1) rate of ethanol elimination and thus rate of acetaldehyde formation, (2) actions of ethanol-derived acetal-dehyde, and (3) ethanol-induced redox effects.

We report five cases of dysfunction of the sinus node in patients suffering from familial amyloidosis with polyneuropathy. The implantation of a pacemaker resulted in symptomatologic relief in all.

We studied the pharmacokinetics of ethanol in the rat rete testis fluid, interstitial fluid, seminiferous tubules, epididymal fluid, and whole testis after 0.75 g/kg and 1.5 g/kg intraperitoneal injections. Ethanol concentration in these tissues was compared to that in capillary and arterial blood. The data was characterized by fitting to a mathematical model. The highest ethanol concentrations in orbital capillary blood were measured 10 min after the injections. Ethanol content in testis homogenate and interstitial fluid did not generally differ from that of orbital blood. However, in rete testis fluid the highest ethanol values were measured at 60 min by the 1.5 g/kg dose and at 30 min by 0.75 g/kg. Ethanol values before this differed from those of capillary blood and interstitial fluid (p less than 0.05-0.001). In seminiferous tubules, the highest ethanol concentration was reached at 20 min, and ethanol content was in general lower than in orbital blood (p less than 0.001-0.01). Ethanol levels in epididymal fluid were comparable to capillary blood. The transportability factor from the model for rete testis was low, which indicates a barrier of penetration of ethanol from blood. In addition, water contents of testicular compartments were calculated. The area under the curve values of rete testis and seminiferous tubules were approximately 10 and 30%, respectively, smaller than that of interstitial fluid, for example. Therefore, the germ cells are somewhat better protected from ethanol than the interstitial cells.

Hepatic and blood acetaldehyde concentrations during ethanol oxidation were determined in C57 and DBA mice. Liver acetaldehyde was determined with the perchloric acid-thiourea method (no artefactual acetaldehyde formation). Levels ranging from 5 to 118 nmole/g were observed. At ethanol concentrations below 50-60 mumole/g, liver acetaldehyde concentrations were higher in DBA compared with C57 mice. A positive correlation was found between the ethanol and acetaldehyde concentration, when ethanol concentration was below 25 (DBA) or 70 mumole/g (C57). At higher ethanol concentrations the correlations tended to become negative. Artefactual acetaldehyde formation during the analytical procedures was obtained with the use of hemolysis, with or without thiourea, and semicarbazide methods for blood acetaldehyde determination. The magnitude of the artefactually formed acetaldehyde was of such order that no conclusions regarding the existence of true in vivo blood acetaldehyde concentrations could be drawn. Earlier reported mice blood acetaldehyde concentrations are suggested to be re-evaluated.

To the Editor: We read with interest the report of the MIST trial,1 designed to answer the intriguing question, “Can elimination of an interatrial shunt mitigate migraine symptoms?” Patent foramen ovale (PFO) closure might be a remedy for thousands of people suffering from migraine. The final report gave a negative answer. Two potential explanations exist for this: Either the PFOs were not closed, or a causal relationship between PFO and migraine with aura does not exist. In our opinion, several procedural issues make it difficult to interpret the results. …

Liver cystolic aldehyde dehydrogenase 1 (ALDH1A1) has been previously associated with both alcohol dependence and alcohol consumption behaviour, and has been implicated in alcohol-induced flushing and alcohol sensitivity in Caucasians. The present study tested for association between ALDH1A1 and alcohol consumption behaviour and susceptibility to problem drinking or alcohol dependence in Finnish cohorts of unrelated male subjects recruited from alcoholism clinical treatment facilities (n = 104) and from the general population (n = 201). All participants completed the Alcohol Use Disorder Identification Test (AUDIT) and were genotyped for eight single nucleotide polymorphisms (SNPs) within or flanking ALDH1A1. To test for association between alcohol consumption behaviour and these polymorphisms, we used generalised linear models and haplotypic analysis. Three SNPs were nominally associated (rs348449, p = 0.043; rs610529, p = 0.013; rs348479, p = 0.025) with the quantitative AUDIT score, which evaluates alcohol consumption behaviour. Two-locus (rs6I0529-rs2288087) haplotype analysis increased the strength of association with AUDIT score (p = 0.00I5). Additionally, rs348449 is highly associated with problem drinking (allelic odds ratio [OR] 7.87, 95 per cent confidence interval [CI] 1.67-37.01) but due to the low minor allele frequency (0.01 and 0.07 in controls and problem drinkers, respectively), more samples are required to validate this observation. Conversely, rs348479 (p = 0.019) and rs6I0529 (allelic OR 0.65, 95 per cent CI 0.43-0.98; genotypic OR 0.32, 95 per cent CI 0.12-0.84) are implicated in alcohol dependence status. This study provides further evidence for a role for ALDH1A1 in alcohol consumption behaviour, including problem drinking and possibly alcohol dependence, in our Finnish population.

Echec d'une therapeutique conventionnelle (par les digitaliques et dimetiques) des inhibiteurs de l'enzyme de conversion de l'angiotensine chez 8 patients souffrant d'insuffisance cardiaque chronique. Etude des benefices apportes a long terme par l'association de la prazosine a ces traitements. Evaluation de ces effets selon le degre de gravite de l'insuffisance cardiaque