Iatrogenic atrial septal defect does not affect acute hemodynamic modifications after transcatheter edge-to-edge repair in patients with functional mitral regurgitation.

OBJECTIVE: The correction of functional mitral regurgitation (FMR) with transcatheter edge-to-edge repair (TEER) can favorably affect patients' hemodynamic profile. However, the procedure requires inter-atrial trans-septal access and the hemodynamic relevance of the residual iatrogenic atrium septal defect (iASD) is still debated. This study aimed at investigating the hemodynamic modifications during TEER with MitraClip, before and after the iASD creation, in patients with heart failure with reduced ejection fraction (HFrEF) and severe FMR. METHODS: Thirty-nine HFrEF patients with 3+ or 4+/4+ FMR were included. Right heart catheterization was performed at baseline after general anesthesia induction and at the end of TEER, both before and after removing the device guiding catheter. RESULTS: Compared with baseline, MitraClip positioning was followed by a significant immediate improvement in cardiac output (respectively: 3.36 vs 5.05 ml/min), pulmonary artery wedge pressure (23.7 vs 18.2 mmHg), mean pulmonary artery pressure (34.4 vs 27.7 mmHg) and pulmonary vascular resistance (3.6 vs 2.2 Wood Units) (all p < 0.001). No further significant modifications occurred after removing the device guiding catheter. CONCLUSIONS: Our data suggest that the acute hemodynamic modifications after TEER are not influenced by the induction of iASD in patients with FMR.

Healing of acute myocarditis with left ventricular assist device: morphological recovery and evolution to the aspecific features of dilated cardiomyopathy.

Dilated cardiomyopathy may result from an acute myocarditis. Little is reported in vivo documenting the progression from the acute inflammatory disease to the healing phase. We describe the consecutive light and electron microscopy studies performed on five myocardial sample series in a 47-year-old female patient who was referred to our hospital with acute myocarditis. She was sustained with left ventricular assist device (LVAD) for 63 days, and then she died of cerebral hemorrhage. The first three consecutive endomyocardial biopsies (days 2, 4, 36 from onset) documented the acute and early healing phase of the inflammatory disease. In the last two biopsies (days 50 and 64 from onset) active inflammation and myocyte necrosis were absent. The histopathological features were those commonly observed in most patients diagnosed with dilated cardiomyopathy, namely myocyte hypertrophy, nuclear size and shape irregularities, and interstitial fibrosis. Overall, the myocyte morphology significantly improved and LVAD support likely contributed to the structural recovery. The major conclusions to be drawn from this case are: 1) the aspecific pathologic findings of dilated cardiomyopathy patients may result from an acute myocardial inflammation; 2) immediate endomyocardial biopsy in patients with clinically diagnosed myocarditis minimizes the risk of missing the diagnosis of inflammatory disease; to this aim a precise definition of "early onset" is especially needed; 3) LVAD support may contribute to the morphological recovery of severely damaged myocytes.

Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy.

Mitochondrial (mt)DNA defects, both deletions and tRNA point mutations, have been associated with cardiomyopathies. The aim of the study was to determine the prevalence of pathological mtDNA mutations and to assess associated defects of mitochondrial enzyme activity in dilated cardiomyopathy (DCM) patients with ultrastructural abnormalities of cardiac mitochondria. In a large cohort of 601 DCM patients we performed conventional light and electron microscopy on endomyocardial biopsy samples. Cases with giant organelles, angulated, tubular, and concentric cristae, and crystalloid or osmiophilic inclusion bodies were selected for mtDNA analysis. Mutation screening techniques, automated DNA sequencing, restriction enzyme digestion, and densitometric assays were performed to identify mtDNA mutations, assess heteroplasmy, and quantify the amount of mutant in myocardial and blood DNA. Of 601 patients (16 to 63 years; mean, 43.5 +/- 12.7 years), 85 had ultrastructural evidence of giant organelles, with abnormal cristae and inclusion bodies; 19 of 85 (22.35%) had heteroplasmic mtDNA mutations (9 tRNA, 5 rRNA, and 4 missense, one in two patients) that were not found in 111 normal controls and in 32 DCM patients without the above ultrastructural mitochondrial abnormalities. In all cases, the amount of mutant was higher in heart than in blood. In hearts of patients that later underwent transplantation, cytochrome c oxidase (Cox) activity was significantly lower in cases with mutations than in those without or controls (P = 0.0008). NADH dehydrogenase activity was only slightly reduced in cases with mutations (P = 0.0388), whereas succinic dehydrogenase activity did not significantly differ between DCM patients with mtDNA mutations and those without or controls. The present study represents the first attempt to detect a morphological, easily identifiable marker to guide mtDNA mutation screening. Pathological mtDNA mutations are associated with ultrastructurally abnormal mitochondria, and reduced Cox activity in a small subgroup of non-otherwise-defined, idiopathic DCMs, in which mtDNA defects may constitute the basis for, or contribute to, the development of congestive heart failure.

Further evidence for the usefulness of the salivary testosterone radioimmunoassay in the assessment of androgenicity in man in basal and stimulated conditions.

Since correct assessment of testicular function and androgenic status in humans requires multiple sampling, a sensitive and accurate radioimmunoassay (RIA) of testosterone (T) was established for male and female saliva samples. This easily collected biological fluid, which contains nonprotein-bound T, may represent an attractive alternative or a complement to total plasma T assays. In saliva samples from 5 normal males, a clear circadian rhythm was observed, and morning concentrations (135 +/- 31 pg/ml) were significantly higher (p less than 0.02) than evening samples (85 +/- 23 pg/ml). In 11 normal females, morning saliva levels were 12.8 +/- 1.8 pg/ml. The levels of T in male saliva, in response to both exogenous T administration (100 mg i.m.) and HCG stimulation (2 X 2,000 IU i.m.), accurately reflected the changes observed in plasma T, and the magnitude of increase in T levels was clearly greater in saliva than in plasma samples during the intramuscular administration of the long-acting T preparation. In males, significant correlations were observed between salivary and plasma T concentrations in morning samples (r = 0.61, p less than 0.01), following HCG stimulation (r = 0.89, p less than 0.05) and during T administration (r = 0.87, p less than 0.05). In women, the correlation at 8 a.m. was also significant (r = 0.82, p less than 0.05).

Determination of fertility interval with ovulation time estimation using differential skin surface temperature (DST) measurement.

Temperature distributions over the breasts of five healthy, young female volunteers using non-pharmaceutical contraceptives were studied over a menstrual cycle to identify "dynamic" temperature points related to E2-induced vascularity and "static" temperature points reflecting the body's core temperature. Corresponding thermometric measurements were analyzed. It was shown during a preliminary study that the DST between a "dynamic" and "static" point, so located, provides advance information on ovulation timing independent of physiologic disturbances and circadian and ambient temperature changes.

PIP: The basal body temperature (BBT) method of ovulation detection has received much attention in the past among natural birth control practitioners and infertility clinics, but it is not capable of determining the ovulation time in advance to estimate the onset of the fertile interval. Thus, the method can be used neither to improve the probability of conception for couples desiring children nor to minimize the abstinence period for natural birth control (NBC) practitioners. In a few studios made on breast temperature changes during the menstrual cycle of a woman, high temperature spots on the skin surface related to vascular activity have been observed around the breasts in the preovulatory peroid, but these could not be correlated with ovulation time in out of laboratory conditions, since the skin temperature is a function of ambient temperature. To overcome this problem, the measurement of "differential skin surface temperature (DST'" between 2 different points of the body is proposed. A study was undertaken on 5 healthy, regularly menstruating, young men volunteers, 25-35 years of age, using only nonpharmaceutical contraceptives (e.g. NBC, diapragms, IUDs). Infrared thermography (IRT) was used to scan the breast and study temperature distributions related to the vascular variations during a menstrual cycle. Based on visual inspection of IRT images, dynamic temperature point B on a warm area just outside the areola and static temperature point C just below the breast (avascular area) were chosen for monitoring. All volunteers recorded their BBT every morning using a commercial mercury fertility thermometer. They also noted the time, drugs consumed, or journey taken, so that proper BBT analysis of the cycle could be subsequently made. As a 2nd phase, 2 oral contraceptive (OC) users underwent the IRT scanning and DST measurement over 1 menstrual cycle for control purposes. The degree of rise in DST was related to the level of plasma estradiol (E2) in the individual patients, and the correlation between them was significant. The changes in DST were statistically significant, compared with the BBT variations. The BBT change due to fever was not reflected in the DST curve of the same volunteer, indicating that in at least 1 case DST was not affected by transient physiologic changes. This could prove to be a significant advantage of the DST as compared with the BBT. The temperature distribution changes were observed (by IRT) to be almost symmetric on the 2 breasts. The study with 2 women using OCs confirmed the high degree of basal vascularization already reported and showed no significant variations in DST. In sum, the DST between a "dynamic" and "static" point, so located, provides advance information on ovulation timing independent of physiologic disturbances and circadian and ambient temperature changes.

Diagnostic strategy in hyperandrogenic syndrome.

Plasma testosterone (T), androstenedione (A), follicle-stimulating hormone, (FSH), luteinizing hormone (LH), prolactin (PRL), and urinary 17-ketosteroids (17-CS) have been measured in 152 women complaining of acne and/or hirsutism. Mean plasma levels of T, A, LH, PRL, and urinary 17-CS were significantly increased as compared to controls. T and/or A were increased in 59% of the cases. T was higher in women with PRL greater than 16 micrograms/l as compared to women with PRL less than 13 micrograms/l. Hirsutism had markedly decreased in 64% and acne in 84% of patients treated with cyproterone acetate.

Amniotic fluid testosterone in prenatal sex determination.

Nonconjugated testosterone levels were measured by radioimmunoassay in samples of amniotic fluid from 60 normal pregnant women between 15 and 32 weeks of gestation. In the male fetuses, the mean +/- SEM amniotic fluid testosterone levels(328 +/- 25 pg/ml) were significantly higher (p less than 0,001) than the concentrations found in the female fetuses (121 +/- 9 pg/ml). The ranges were from 155 to 730 and from 46 to 240 pg/ml respectively, which shows an overlap area of the values between the sexes from 155 to 240 pg/ml. The results emphasize the potential interest of amniotic testosterone in the determination of fetal sex.

Effects of chronic neuroleptic therapy on human PRL secretion and testicular function.

Correlation between secretion of testicular steroids and plasma prolactin (PRL) levels, before and during bromocriptin treatment, was studied in 20 psychiatric patients under neuroleptic therapy for two years or longer. Eleven of them were under additional treatment with antiparkinson drugs (AP group). Plasma PRL, testosterone (T), 5 alpha dihydrotestostérone (DHT), 17 beta-estradiol (E2), 17 alpha OH-progestérone (17 alpha OHP), and dehydroepiandrosterone-sulfate (D-S) were measured by specific RIA both at basal level and in response to testicular stimulation by hCG. Mean basal PRL levels were normal in the patients under neuroleptic treatment along (Ne group), and slightly elevated in the AP group. In the Ne group, an unexpected, significant increase occurred in mean plasma PRL during the hCG stimulation, before bromocriptine treatment. Mean basal steroid levels were normal in both groups. The testicular responses to hCG, as reflected by the T, E2, 17 alpha OHP, and DHT mean plasma levels, were within the normal ranges in the AP group; in the Ne group, however, T and DHT displayed a subnormal mean increase, while E2 and 17 alpha OHP responses were within the normal range. These results suggest that some modifications of the enzymatic activity for testicular steroidogenesis could be induced in the patients under neuroleptic treatment alone. Moreover, a significant reverse correlation was found between PRL and T basal in both group; this correlation disappeared during the bromocriptine treatment.

New aspects of androgens, prolactin, and ACTH interaction in men.

Some endocrine effects of prolactin (PRL), ACTH, and corticosteroids in testicular function were evaluated by measuring, in normal men, the effects of short-term experimental stimulation and suppression of either plasma PRL levels or adrenal function on plasma androgen profile. PRL levels were increased by administration of metoclopramide or sulpiride or suppressed with bromocryptine. Long-acting testosterone (T) was injected at 8 a.m. on one day in a control period and during a 9-day period of metoclopramide administration. PRL increase was accompanied by a rise in plasma 17-hydroxyprogesterone and T, whereas PRL suppression induced an increase in 5 alpha-dihydrotestosterone (DHT) plasma levels. Peripheral converions of T into DHT and androstenedione, noted after T injection, decreased during concomitant metoclopramide administration. Plasma testicular androgen levels were lowered after long-acting ACTH injections as well as after 24-hr cortisol administration, but the metoclopramide-induced PRL increase appeared to prevent the suppressive effects of ACTH on plasma T. A low-dose dexamethasone treatment did not modify testicular androgen levels. Experimentally induced hyperprolactinemia may have a stimulatory effect on testicular androgen secretion as well as a lowering action on 5 alpha reduction and oxidative T metabolism in man. On the other hand, ACTH-induced androgen suppression seems to be mediated through high circulating levels of corticosteroids; furthermore, PRL and corticosteroids might have reciprocal influences that modulate their effects on testicular function.

Study on the binding of dihydrotestosterone, testosterone and oestradiol with sex hormone binding globulin.

Saturation studies on sex hormone binding globulin (SHBG) were performed with increasing levels of the three steroids: dihydrotestosterone (DHT), testosterone (T) and oestradiol (E2) in normal female sera. The curves obtained showed the clearly increasing SHBG affinity for E2, T and DHT, respectively. With T as saturating ligand, the mean values of SHBG binding capacity in normal and pathological sera, expressed as 10(-8) M SHBG were, for normal women, 5.87 +/- 0.2, for normal men, 3.69 +/- 0.1 and for hirsute women, 5.05 +/- 0.2. In hirsutism, SHBG levels were measured together with T and DHT levels. Hyperandrogenia was often better reflected by the T/SHBG ratio than by T levels alone. SHBG binding capacity, measured in pregnancy from the 7th to the 40th week, increased progressively as far as the 30th week. Values up to 5 times those of the mean value of the cycle were observed at the end of pregnancy. Variations in DHT, T and E2 binding as functions of SHBG concentrations, were also studied by adding a constant amount of each steroid to increasing SHBG concentrations in serum. DHT showed the greatest binding capacity, followed by T and then E2. Since the unbound fractions of T and DHT are believed to be biologically active, and since T and DHT are more sensitive than E2 to SHBG variations, the results obtained further support the hypothesis that SHBG plays an important role in the sex steroids balance.

[Effect of the steroid sex hormones on the LH and FSH responses to LHRH in the normal subject]. / Action des stéroïdes sexuels sur les réponses LH et FSH au LHRH chez le sujet normal

In man both basal gonadotrophin levels and the pituitary responses to LHRH remained relatively constant throughout life. In women the pituitary sensitivity varied in the menstrual cycle due to the typical cyclic variation of oestradiol and progesterone. The max delta LH increase to 100 mug LHRH was observed in the periovulatory period (183 +/- 41 mU/ml); it was also significantly higher in the luteal (49 +/- 7 mu/ml) than in the early follicular phase (18 +/- 3 mU/ml). The effect of exogenous sex steroid hormones taken as contraceptive drugs was then studied in 15 women. Significantly lower LH and FSH basal values as well as responses to LHRH were observed in 8 normal women under oral combined contraceptives. Conversely, in 7 women under oral sequential contraceptives, basal LH and FSH remained in the normal range. The LH-FSH responses were increased and delayed when these tests were performed during the period of estrogen treatment. Thus, with combined oral contraceptives, constant and high levels of estrogens and progesterone not only inhibit the LH peak, but also decrease the basal LH-FSH levels and responses to releasing hormone. Conversely, with sequential oral contraceptives, the low level of estradiol does not inhibit these responses and even enhances them. In menopausal women both basal and gonadotrophin responses to LHRH were increased indicating an important pituitary reserve. In menstruating women a significant estradiol increase is observed 2 and 4 hours after a 100 mug LHRH injection, both during the follicular and the luteal phases whereas progesterone increases only in the luteal phase. In men, testosterone was found to increase 4 hours after a 100 mug LHRH injection. These studies show that in normal subjects, sex steroid hormones are important regulators of the sensitivity of the pituitary responsiveness to releasing hormone.

PIP: The effect of exogenous sex steroid hormones taken as contraceptives was studied in 15 women. Significantly lower luteinizing hormone (LH) and follicle stimulating hormone (FSH) basal values as well as responses to LH releasing hormone (LH-RH) were observed in 8 normal women under combination oral contraceptives. Conversely, in 7 women taking sequential oral contraceptives, basal LH and FSH remained within the normal range. The LH-FSH responses were increased and delayed when the tests were performed during the period of estrogen treatment. Thus, with combination oral contraceptives, constant high levels of estrogens and progesterone inhibit the LH peak and also decrease the basal LH-FSH levels and responses to the releasing hormone, while with sequential drugs the low level of estradiol does not inhibit such responses and even enhances them. In menopausal women, both basal and gonadotropin responses to LH-RH were increased, indicating a considerable pituitary reserve. In menstruating women, a significant estradiol increase is observed 2 and 4 hours after a 100 mcg injection of LH-RH both during the follicular and the luteal phases, whereas progesterone increases only in the luteal phase. In men, testosterone was found to increase 4 hours after a 100 mcg injection of LH-RH. The findings show that in normal subjects sex steroid hormones are important regulators of the sensitivity of the pituitary response to the releasing hormone.

[Plasma concentration of phenytoin in epileptics--importance for the clinician]. / Concentration plasmatique de phénytoïne chez les épileptiques==intérêt pour le clinicien

Plasma concentrations of diphenylhydantoin were determined by the method of Wallace (double extraction, spectrophotometry) in 150 samples taken from 121 epileptic patients. They correlated well with those determined by gas chromatography, were not dose-dependent and were often below 10 mul/ml. They were above 20 mul/ml in 6 patients with CNS intoxication. These determinations were also useful for detecting patients who did not take the drug as prescribed (14 suspected cases, 4 confirmed). However, blood levels did not seem to offer an accurate index of the effectiveness of diphenylhydantoin.