[W. D. Winnicott and the transitional object in infancy]. / Winnicott W.D. e la transizionalità negli affetti, nel gioco e negli oggetti.

Donald Winnicott (1896-1971), specialist in children's diseases, psychology and psychotherapy, tried to put together his experience in all these fields. His theories can be put between the orthodox psychoanalytic thought and a "relational" paediatrics. He made his research on the "global reality" of child rather than being interested in the "internal objects". Both the orthodox analysts, who condemned his theories, and the specialists in children's diseases, who didn't recognize the scientific aspect of his genius, criticised and opposed Winnicott. Even if sometimes his theories have not an organic unity, they are the result of very detailed clinical observations, which are supported by a large experience with children at the Paddington Green Children Hospital and the Queen's Hospital for Children in London. With "transition", Winnicott means an intermediate development area between the psychic and external reality. There, we can find the "transitional object", which is the first element leading the child to face the external reality through the creation of symbols. Winnicott goes over the idea of the binomial mother-child, intended as instinctive development, and underlining the importance of real experiences. In his opinion, in the child development one has to stress the concept of "need" instead of that of "desire". A good environment and the empathic contact with "a fairly good mother", cause the passage from the primary narcissism to the object relationships. A fairly good mother must be able to perform holding, handling, and object presenting. Her duty is that of gradually undeceiving, and to do it she must give a sufficient opportunity of illusion. The mother, offering the right opportunity of illusion, puts the basis of symbols. Subsequently, she will go on a gradual disillusion. Winnicott disagrees Klein's ideas by stating that "playing is therapeutic in its own aspect", seeing it as a potential space between mother and child, which will become the place of analysis and transfer and, after on, that of cultural experience.

Exaggerated QT prolongation after cardioversion of atrial fibrillation.

OBJECTIVES: The purpose of this study was to test the hypothesis that the extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardioversion compared with during atrial fibrillation (AF). BACKGROUND: Anecdotes suggest that when action potential-prolonging antiarrhythmic drugs are used for AF, excessive QT prolongation and torsades de pointes (TdP) often occur shortly after sinus rhythm is restored. METHODS: QT was measured in nine patients with AF who received two identical infusions of dofetilide: 1) before elective direct current cardioversion and 2) within 24 h of restoration of SR. RESULTS: During AF, dofetilide did not prolong QT (baseline: 368 +/- 48 ms vs. drug: 391 +/- 60, p = NS) whereas during SR, QT was prolonged from 405 +/- 55 to 470 +/- 67 ms (p < 0.01). In four patients (group I), the SR dofetilide infusion was terminated early because QT prolonged to >500 ms, and one patient developed asymptomatic nonsustained TdP. The remaining five patients (group II) received the entire dose during SR. Although deltaQT was greater in group I during SR (91 +/- 22 vs. 45 +/- 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the two groups (2.72 +/- 0.96 vs. 2.77 +/- 0.25 ng/ml), and in AF (2.76 +/- 1.22 ng/ml). DeltaQT in SR correlated inversely with baseline SR heart rate (r = -0.69, p < 0.05), and QT dispersion developing during the infusion (r = 0.79, p < 0.01). CONCLUSIONS: Shortly after restoration of SR, there was increased sensitivity to QT prolongation by this I(Kr)-specific blocker. Slower heart rates after cardioversion and QT dispersion during treatment appear to be important predictors of this response.

Modulation of effect of dietary salt on prehepatic first-pass metabolism: effects of beta-blockade and intravenous salt loading.

We previously demonstrated that increased dietary salt markedly decreases plasma quinidine concentrations shortly after p.o. dosing, without an effect on the drug's terminal elimination half-life or concentrations after i.v. administration. These findings suggest an effect of dietary salt on intestinal metabolism or transport of the drug. Because one effect of salt loading is sympathetic inhibition, we examined the effect of beta-adrenoceptor blockade on salt-related changes in quinidine disposition. Furthermore, we examined whether the action of salt is local or systemic by determining the effect of salt loading by the i.v. route. To assess the effect of beta-blockade, quinidine disposition was studied in eight normal volunteers after a single p.o. dose of quinidine; data were obtained after 1 week on a high-salt diet (400 mEq/day) and 1 week on a low-salt diet (10 mEq/day) during chronic nadolol and compared with those previously obtained in the same subjects without the beta-blocker. beta-Blockade had no effect on oral clearance during the high-salt diet [0.28 +/- 0.1 (quinidine + nadolol) versus 0.30 +/- 0.2 liters/h/kg (quinidine alone)] but increased clearance on the low-salt diet from 0.23 +/- 0.1 to 0.29 +/- 0.1 liters/h/kg (p <. 05). For the i.v. salt study, the disposition of single p.o. and single i.v. doses of quinidine was determined on two occasions in eight subjects: once during a low-salt diet (10 mEq/day) and once during the same diet, supplemented by 400 mEq/day NaCl i.v. for 8 days. In contrast to our findings after p.o. salt loading, i.v. salt loading did not alter the pharmacokinetics of p.o. quinidine. Taken together, these data implicate a local alteration of drug-metabolizing activity and/or drug transport in the intestinal mucosa as the major effect of dietary salt on the disposition of p.o. quinidine and further suggest that beta-adrenergic activation by a low-salt diet is one component of a signaling pathway whereby intestinal drug disposition is suppressed, resulting in increased oral bioavailability.

Modulation by dietary salt of verapamil disposition in humans.

BACKGROUND: The intestine is an increasingly well-recognized site of first-pass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes extensive first-pass metabolism. METHODS AND RESULTS: Eight normal volunteers received 120 mg of racemic verapamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterated verapamil with the morning oral dose on days 7, 14, and 21. Each study day was preceded by 7 days on a fixed-salt diet: in 5 subjects, the initial study was conducted during a low-salt (10 mEq/d) diet, the second study during a high-salt (400 mEq/d) diet, and the third during a low-salt diet, whereas in the other 3 subjects, the sequence of diets was reversed. Plasma concentrations of both unlabeled enantiomers (ie, from oral therapy) were significantly (P<0.05) lower during the high-salt phase (eg, mean area under the time-concentration curve [0 to 12 hours] for S-verapamil: 7765+/-2591 ng. min. mL-1 [high salt] versus 12 514+/-3527 ng. min. mL-1 [low salt], P<0.05). Peak plasma concentrations were significantly lower and the extent of PR interval prolongation significantly blunted with the high-salt diet. In contrast, data with labeled drug (ie, reflecting the intravenous route) were nearly identical for the 2 diets. CONCLUSIONS: These data indicate that a clinically important component of presystemic drug disposition occurs at the prehepatic (presumably intestinal) level and is sensitive to dietary salt.

Cardiac autonomic patterns preceding occasional vasovagal reactions in healthy humans.

BACKGROUND: The wide range of clinical presentation of orthostatic vasovagal syncope suggests different underlying changes in the cardiac autonomic modulation. METHODS AND RESULTS: To evaluate the beat-by-beat modifications in the neural control of heart period preceding a syncopal event, we studied RR interval variability in 22 healthy subjects who experienced fainting for the first time during a 90 degrees head-up tilt and in 22 control subjects by means of time-variant power spectral analysis. Sympathetic and vagal modulations to the sinoatrial node were assessed by the normalized power of the low-frequency (LF, approximately 0.1-Hz) and high-frequency (HF, approximately 0.25-Hz) oscillatory components of RR variability. When the patients were supine, no differences were observed in the hemodynamic and spectral parameters of the 2 groups. During the tilt procedure, RR, LFNU, and HFNU (NU=normalized units) values were relatively stable in control subjects. During early tilt (T1), subjects with syncope had reduced RR intervals compared with control subjects. In 13 subjects with syncope, RR decreased while LFNU and LF/HF increased in the last minute of tilt before syncope (T2). Conversely, in the remaining 9 fainters, LFNU and LF/HF decreased from T1 to T2 and HFNU increased slightly. CONCLUSIONS: Two different patterns may be recognized in the cardiac autonomic changes preceding an occasional vasovagal event, namely, one characterized by a progressive increase of the marker of cardiac sympathetic modulation up to the onset of syncope, the other by a sympathetic inhibition with an impending vagal predominance. The recognition of different pathophysiological mechanisms in fainters may have important therapeutic implications.

Dietary salt increases first-pass elimination of oral quinidine.

BACKGROUND: Some cytochrome P450 (CYP) enzymes, including CYP3A, are expressed not only in the liver but also in the intestine; the latter may therefore be an important site of drug disposition. Animal data suggests that dietary salt modulates expression of renal CYPs. We therefore hypothesized that intestinal CYP3A may be similarly modulated by dietary salt. METHODS: The effect of changes in dietary salt on the disposition of two CYP3A substrates, quinidine (administered orally and intravenously) and 14C-erythromycin (administered intravenously) were determined after normal volunteers were given high-salt (400 mEq/day) and low-salt (10 mEq/day) diets for 7 to 10 days each. RESULTS: Plasma concentrations after oral quinidine were significantly lower during the high-salt phase, with the difference between the two treatments attributable to changes within the first 1 to 4 hours after administration. For example, the area under the plasma concentration-time curve for the first hour after drug administration was 0.56 +/- 0.38 microgram.hr/ml for the high-salt diet compared with 1.57 +/- 0.60 micrograms.hr/ml for the low-salt diet (p < 0.05). Similarly, the peak plasma concentration (Cmax) achieved was lower and the time to reach Cmax was later for the high-salt diet (p < 0.05). In contrast, the terminal phase elimination half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug. The erythromycin breath test was unaffected by the dietary treatments. CONCLUSIONS: These results indicate an effect of dietary salt on the presystemic disposition of orally administered quinidine. Although the mechanism(s) of CYP3A activity modulation is unknown, this finding may be important in determining drug availability in conditions associated with abnormal salt homeostasis.

Loss of quinidine gluconate injection in a polyvinyl chloride infusion system.

The effect of a polyvinyl chloride (PVC) i.v. administration system on the availability of quinidine gluconate was studied. Quinidine gluconate diluted in 5% dextrose injection was administered intravenously to five healthy volunteers via conventional PVC infusion sets, and the subjects received oral quinidine sulfate two days later. The mean +/- S.D. oral bioavailability of quinidine was, unexpectedly, greater than 100% (147 +/- 44%). To test the possibility that this occurred because of reduced delivery of i.v. quinidine, the percentage of drug delivered via two systems was evaluated in simulation studies, one involving a conventional PVC administration set and the other a glass syringe attached to shorter PVC tubing and a winged i.v. catheter. Spectrophotometric analysis revealed a 5-7% reduction in absorbance associated with loss of quinidine in the PVC infusion bag and a further 34-38% reduction in absorbance attributable to quinidine loss in the PVC tubing. However, with the winged i.v. catheter system the loss was reduced to less than 3%. More than 40% of a dose of quinidine gluconate was lost when the drug was administered with a conventional PVC i.v. administration set. Drug loss was reduced by using a winged i.v. catheter and shorter tubing.

Mechanical effects of respiration and stepping on systolic arterial pressure variability during treadmill exercise.

AIM: To evaluate the changes produced by maximal dynamic exercise in the rhythmic components of systolic arterial pressure variability. PATIENTS AND METHODS: We studied seven normotensive subjects during different levels of a modified treadmill test (Bruce protocol, up to stage 4). Arterial pressure was measured directly by a high-fidelity microtip pressure transducer. Spectral analysis provided two main oscillatory components of systolic arterial pressure variability, a low-frequency component related to the sympathetic-mediated neural control of vasomotion and a high-frequency component reflecting the mechanical effects of respiration on blood pressure. RESULTS: The low-frequency component increased at the beginning of exercise and remained stable thereafter, while the high-frequency component increased progressively. A third rhythmic component (very high frequency) with a frequency higher than respiration and synchronous with the rate of the subjects' footsteps, which was undetectable on a visual inspection of analog tracings, became progressively more apparent, reaching its maximum at exercise stage 4. CONCLUSIONS: These findings emphasize the importance of high-fidelity techniques and computer analysis for the evaluation of arterial pressure variability in dynamic conditions.

Early and late effects of exercise and athletic training on neural mechanisms controlling heart rate.

OBJECTIVE: This study addresses the long term and short term effects of heavy dynamic exercise on neural control of heart rate. METHODS: A group of healthy controls was compared with (1) a group of trained athletes during a period of yearly rest (detrained) and (2) a group of trained athletes at the peak of their training routine. Additionally, a group of 10 controls was studied 1, 24, and 48 h after a single bout of maximal dynamic exercise. Spectral analysis of RR interval variability provided markers of sympathetic (low frequency, LF, 0.10 Hz) and vagal (high frequency, HF, 0.25 Hz) modulation of the sinoatrial node. RESULTS: (1) In detrained athletes resting bradycardia was accompanied by a predominant HF rhythmic component suggestive of a prevailing vagal tone. (2) Trained athletes showed a resting bradycardia together with high LF values, thus suggesting a more complex neural interaction modulating heart rate. An additional longitudinal part of the study, performed on a group of detrained athletes who were examined for the second time after resuming training, confirmed the finding of a prevailing LF component in resting conditions. (3) In the 10 control subjects maximal dynamic exercise induced an increase in LF which outlasted the cessation of exercise up to 24 h, suggesting a persistent sympathetic activation. (4) Passive tilt, a manoeuvre which enhances sympathetic drive, produced a greater enhancement of the LF component in trained athletes than in control subjects. CONCLUSIONS: The cardiac sympathetic excitation outlasting heavy dynamic exercise may explain the coexistence of training bradycardia with signs of enhanced sympathetic activity in trained champion athletes.

Circadian changes in vascular sympathetic activity in ambulant subjects.

In 10 ambulant subjects we studied the circadian changes in sympathetic vasomotor control as assessed by the spectral power of the 0.1-Hz low-frequency component of systolic arterial pressure variability measured with a Millar phi 3F tip transducer. The low-frequency component was higher during the daytime, while the subjects were performing light physical activity, and lower during the night, thus paralleling the circadian systolic blood pressure pattern. However, the morning low-frequency rise preceded the blood pressure increase by about 3 h, suggesting that vasometer control and blood pressure control are at least partly related to different mechanisms.

Changes in autonomic regulation induced by physical training in mild hypertension.

The adaptive effects of physical training on cardiovascular control mechanisms were studied in 11 subjects with mild hypertension. In these subjects we assessed the gain of the heart period-systolic arterial pressure relationship in the unfit and the fit state by using 1) an open loop approach, whereby the gain is expressed by the slope of the regression of heart period as a function of systolic arterial pressure, during a phenylephrine-induced pressure rise and 2) a closed loop approach with proper simplification, whereby the gain is expressed by the index alpha, obtained through simultaneous spectral analysis of the spontaneous variabilities of heart period and systolic arterial pressure. Both methods indicated that training significantly increased the gain of the relationship between heart period and systolic arterial pressure at rest and reduced arterial pressure and increased heart period significantly. This gain was drastically reduced during bicycle exercise both in the unfit and fit state. In a second group of normotensive (n = 7; systolic pressure, 133 +/- 3 mm Hg) and hypertensive (n = 7; systolic pressure, 180 +/- 10 mm Hg) subjects undergoing 24-hour diagnostic continuous electrocardiographic and high fidelity arterial pressure monitoring, the index alpha was significantly reduced in the hypertensive group at rest. Furthermore, when analyzed continuously over the entire 24-hour period, this index underwent minute-to-minute changes with lower values during the day and higher values during the night. We propose the index alpha as a quantitative indicator of the changes in the gain of baroreceptor mechanisms occurring with physical training in mild hypertension and during a 24-hour period in ambulatory subjects.

Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog.

In 57 normal subjects (age 20-60 years), we analyzed the spontaneous beat-to-beat oscillation in R-R interval during control recumbent position, 90 degrees upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) beta-adrenergic receptor blockade. Automatic computer analysis provided the autoregressive power spectral density, as well as the number and relative power of the individual components. The power spectral density of R-R interval variability contained two major components in power, a high frequency at approximately 0.25 Hz and a low frequency at approximately 0.1 Hz, with a normalized low frequency:high frequency ratio of 3.6 +/- 0.7. With tilt, the low-frequency component became largely predominant (90 +/- 1%) with a low frequency:high frequency ratio of 21 +/- 4. Acute beta-adrenergic receptor blockade (0.2 mg/kg IV propranolol) increased variance at rest and markedly blunted the increase in low frequency and low frequency:high frequency ratio induced by tilt. Chronic beta-adrenergic receptor blockade (0.6 mg/kg p.o. propranolol, t.i.d.), in addition, reduced low frequency and increased high frequency at rest, while limiting the low frequency:high frequency ratio increase produced by tilt. Controlled respiration produced at rest a marked increase in the high-frequency component, with a reduction of the low-frequency component and of the low frequency:high frequency ratio (0.7 +/- 0.1); during tilt, the increase in the low frequency:high frequency ratio (8.3 +/- 1.6) was significantly smaller. In seven additional subjects in whom direct high-fidelity arterial pressure was recorded, simultaneous R-R interval and arterial pressure variabilities were examined at rest and during tilt. Also, the power spectral density of arterial pressure variability contained two major components, with a relative low frequency:high frequency ratio at rest of 2.8 +/- 0.7, which became 17 +/- 5 with tilt. These power spectral density components were numerically similar to those observed in R-R variability. Thus, invasive and noninvasive studies provided similar results. More direct information on the role of cardiac sympathetic nerves on R-R and arterial pressure variabilities was derived from a group of experiments in conscious dogs before and after bilateral stellectomy. Under control conditions, high frequency was predominant and low frequency was very small or absent, owing to a predominant vagal tone. During a 9% decrease in arterial pressure obtained with IV nitroglycerin, there was a marked increase in low frequency, as a result of reflex sympathetic activation.(ABSTRACT TRUNCATED AT 400 WORDS)

Continuous recording of direct high fidelity arterial pressure and electrocardiogram in ambulant patients.

A system providing high quality direct arterial blood pressure recordings and electrocardiograms in ambulatory patients was devised using a modified commercially available Holter type magnetic tape recorder together with a microminiature Millar (3F) tip transducer. This system did not require a perfusion line and solved the major drawbacks of other available systems. Pressure and electrocardiographic data were fed directly from the playback unit into a minicomputer for automatic beat to beat waveform analysis. Thus the blood pressure and RR interval variability signals could be simultaneously analysed with autoregressive modelling techniques to provide a quantitative estimate of sympathovagal balance in ambulant patients. The system was reliable, simple, and safe to use.

Simultaneous analysis of beat by beat systemic arterial pressure and heart rate variabilities in ambulatory patients.

The analysis of power spectral density (PSD) or RR variability in the electrocardiogram (ECG) has suggested that, in the early phase of essential hypertension, sympatho-vagal interaction is characterized by a sympathetic predominance. Recently, we have developed a high fidelity, direct arterial pressure ambulatory recording system which allows a beat by beat computer analysis of arterial pressure and heart rate. A microminiature tip transducer (Millar, diameter 0.8 mm) is inserted percutaneously into the radial artery and connected to a Holter two-channel magnetic tape recorder. The tip transducer has a wide band pass (> 1 kHz), excellent stability (congruent to 2 mmHg/24 h) and does not require a perfusion line. The overall frequency response of the entire recording-reproducing system is better than 20 Hz (-3 dB). The ECG and pressure signals are analysed with automatic autoregressive modelling algorithms to provide a quantitative estimate of blood pressure and heart rate variability through the computation of the PSD. In seven hypertensive patients, systolic arterial pressure and variance were higher during the day (157 +/- 9 mmHg and 122 +/- 9 mmHg2) than during the night (122 +/- 4 mmHg and 30 +/- 3 mmHg2). The PSD of RR and of systolic arterial pressure consisted of a predominant low frequency peak (congruent to 0.09 cycles/beat) during the day, and two peaks at low and high (congruent to 0.25 cycles/beat) frequency during the night. While RR variance was similar during both day- and night-time, a predominant low frequency peak was observed during the day.(ABSTRACT TRUNCATED AT 250 WORDS)