Retrieving fear memories, as time goes by .

Research in fear conditioning has provided a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, our understanding of the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring some clarity and raise awareness about the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points following auditory fear conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus (PVT) for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change with time, and consider the functional strategy of recruiting structures not previously considered as part of the retrieval circuit.

Lentivirus-mediated gene transfer to the respiratory epithelium: a promising approach to gene therapy of cystic fibrosis.

Gene therapy of cystic fibrosis (CF) lung disease needs highly efficient delivery and long-lasting complementation of the CFTR (cystic fibrosis transmembrane conductance regulator) gene into the respiratory epithelium. The development of lentiviral vectors has been a recent advance in the field of gene transfer and therapy. These integrating vectors appear to be promising vehicles for gene delivery into respiratory epithelial cells by virtue of their ability to infect nondividing cells and mediate long-term persistence of transgene expression. Studies in human airway tissues and animal models have highlighted the possibility of achieving gene expression by lentiviral vectors, which outlasted the normal lifespan of the respiratory epithelium, indicating targeting of a 'stem cell' compartment. Modification of the paracellular permeability and pseudotyping with heterologous envelopes are the strategies currently used to overcome the paucity of specific viral receptors on the apical surface of airway epithelial cells and to reach the basolateral surface receptors. Preclinical studies on CF mice, demonstrating complementation of the CF defect, offer hope that lentivirus gene therapy can be translated into an effective treatment of CF lung disease. Besides a direct targeting of the stem/progenitor niche(s) in the CF airways, an alternative approach may envision homing of hematopoietic stem cells engineered to express the CFTR gene by lentiviral vectors. In the context of lentivirus-mediated CFTR gene transfer to the CF airways, biosafety aspects should be of primary concern.

Interactive action of the white-coat effect and the blood pressure levels on cardiovascular complications in hypertension.

PURPOSE: This study was undertaken to investigate whether there is a relationship between the white-coat effect and the cardiovascular complications of hypertension. PATIENTS AND METHODS: In 1,013 consecutive borderline to severe hypertensive outpatients (889 men) with a mean age (+/-SE) of 33.6 +/- 0.5 years and a mean office blood pressure of 152.3 +/- 0.6/95.5 +/- 0.4 mm Hg, blood pressure was measured by noninvasive 24-hour ambulatory monitoring. Target organ damage was assessed by electrocardiogram, chest X-ray, echocardiography, and ophthalmoscopy. The degree of target organ damage and of left ventricular hypertrophy was assessed in the subjects divided according to the levels of their daytime blood pressure and the extent of their white-coat effect. RESULTS: The subjects with a high white-coat effect showed a greater degree of hypertensive complications than those with intermediate or a low white-coat effect. The significant association between the white-coat phenomenon and the hypertensive complications was confirmed by the results of stepwise regression analyses, where sex, age, duration of hypertension, and ambulatory blood pressure were added to the model. A two-way ANOVA showed that both ambulatory blood pressure and the white-coat effect were related to the degree of target organ damage and to left ventricular hypertrophy. Moreover, daytime blood pressure and the white-coat effect showed an interactive effect on hypertensive complications, as the influence of the white-coat effect on end organs increased with increasing levels of ambulatory blood pressure. CONCLUSIONS: The present results show that the white-coat effect is related to the degree of hypertensive complications and that this association is stronger in the subject with more severe hypertension.

[Relationship between blood pressure determination anxiety and hypertensive complications]. / Relazione tra reazione d'allarme alla misurazione pressoria e complicanze ipertensive.

To assess the clinical significance of the reaction to blood pressure measurement, 1,013 (889 men) borderline to severe hypertensive patients, enrolled between 1984 and 1993, were studied. Their mean age (+/- SE) was 33.6 +/- 0.46 (range 16-75 years) and their mean office blood pressure (+/- SE) was 152.3 +/- 0.56/95.5 +/- 0.39 mmHg. All subjects underwent ambulatory blood pressure monitoring, ECG and fundoscopy. On the basis of the latter two tests a target organ damage score was calculated, from 0 (no abnormalities) to 5 (maximum severity). In 731 patients an echocardiogram was also performed. The white-coat effect was assessed by measuring the regression of office blood pressure on ambulatory blood pressure and calculating the residual office blood pressure. The subjects with high residual blood pressure showed a greater degree of age-adjusted target organ damage compared to those with intermediate or low residual blood pressure (systolic p < 0.0001; diastolic p = 0.04). Age-adjusted left ventricular mass was influenced by residual diastolic blood pressure (p < 0.0001). In a stepwise multiple regression analysis, where age, ambulatory blood pressure levels, sex and duration of hypertension were added to the model, residual blood pressure showed a relationship with the degree of target organ damage and left ventricular mass. In conclusion, the present results show that the white-coat-effect is not innocent, as it is associated with a high degree of cardiovascular abnormalities.

In primary aldosteronism the circadian blood pressure rhythm is similar to that in primary hypertension.

To investigate whether the 24-hour blood pressure (BP) profile of primary aldosteronism differs from that of primary hypertension, ambulatory BP monitoring was performed in 11 patients with primary aldosteronism (9 with an adrenal adenoma and 2 with idiopathic hyperaldosteronism) and in 11 primary hypertensives, matched for sex (5M,6F), age (mean: 52 vs 49 yrs) and casual BP. We found no difference in 24-hour BP, nocturnal BP fall, BP variability (standard deviation and peaks of pressure) response to postural changes (lying-standing BP) between the two groups (all p values n.s.). Within the patients with primary aldosteronism no correlation was observed between BP, plasma renin activity, blood and urine aldosterone levels, blood and urine K+, and size of the tumour. Thus, at variance with previous reports, these results show that diurnal rhythm of BP and BP variability are similar in primary aldosteronism and primary hypertensives with similar demographic features and causal BP levels. They also show that an orthostatic fall of BP is not a common feature in this disease.

Sequelae of acute hypoglycaemia on 24 hour blood pressure and metabolic parameters in normal and type 1 (insulin-dependent) diabetic individuals.

This study was performed to assess possible delayed after-effects of acute hypoglycaemia on blood pressure (BP) and heart rate (HR) over a 24-h period. Eleven insulin-dependent diabetic patients and 11 sex, age, and body mass index matched non-diabetic subjects were studied. Blood pressure was measured using a non-invasive ambulatory blood pressure monitor following acutely induced hypoglycaemia in the morning. No significant differences were observed in 24-h systolic and diastolic BP and HR in either groups, between the day when hypoglycaemia was induced and the day when plasma glucose was kept normal. In diabetic patients, hypoglycaemia induced a temporary but significant fall in mean BP (-7 +/- 1 mmHg vs -2 +/- 2; p < 0.05). Plasma glucose levels were significantly higher in insulin-dependent diabetic patients following hypoglycaemia than in those observed during the reference test. This study demonstrates that acute hypoglycaemia in insulin-dependent diabetic subjects does not cause significant alterations in 24-h BP in either diabetic or normal subjects.

Effect of timing of administration on the plasma ACE inhibitory activity and the antihypertensive effect of quinapril.

To assess whether timing of administration can influence the antihypertensive effect of quinapril, 18 patients with hypertension were studied with noninvasive ambulatory blood pressure monitoring. Quinapril, 20 mg, was given at 8 AM or 10 PM for 4 weeks in a double-blind crossover fashion. To study the pattern of angiotensin converting enzyme (ACE) inhibition with the two treatment regimens, plasma ACE activity was measured in seven subjects 2, 4, 8, 12 and 24 hours after quinapril administration. The 24-hour blood pressure profiles showed a more sustained antihypertensive action with the evening administration of quinapril compared with the morning administration of quinapril; as with the morning administration, a partial loss of effectiveness was observed during nighttime hours. Measurement of ACE activity showed that evening administration caused a less pronounced but a more sustained decline of plasma ACE. These findings show that 20 mg quinapril given once daily is effective in lowering blood pressure levels throughout a 24-hour period. The evening administration seems to be preferable because it causes a more favorable modulation of ACE inhibition and therefore determines a more homogeneous 24-hour blood pressure control.

[Clinical significance of blood pressure response to posture]. / Significato clinico della risposta pressoria all'ortostatismo.

To assess the clinical significance of the blood pressure reaction to orthostatic posture, 55 normotensives and 369 subjects with different degrees of hypertension were studied with non-invasive 24-hour blood pressure monitoring. During the recordings blood pressure response to standing was evaluated at 8 a.m., and at 2, 4 and 7 p.m. All subjects were attributed a target organ damage score on the basis of ECG, chest x-ray and fundoscopic findings. To assess whether the orthostatic reaction may represent a marker for the severity of hypertension, subjects were divided into 4 classes of increasing blood pressure levels, and each class was further subdivided into two groups of subjects with orthostatic reaction above and below the mean value. On average, blood pressure rose by 2.7 +/- 9/7.2 +/- 7 mmHg while standing up, an increase which was inversely correlated to that of heart rate (p < 0.05). The orthostatic response was substantially constant throughout daytime hours. The systolic orthostatic change from lying to standing was directly correlated with age (p < 0.02) and average daytime blood pressure (p < 0.01), and inversely correlated with lying blood pressure immediately before standing up (p < 0.001). Both systolic (p < 0.05) and diastolic (p < 0.01) pressure responses to standing were related to the day-night blood pressure difference and to the standard deviation from mean daytime blood pressure. The degree of target organ damage was not significantly greater in the 4 groups of subjects with high orthostatic response compared to those with low response. The present results show that the pressure reaction to orthostatic stress is constant throughout daytime, even though a large intraindividual variability in the extent of the response is present. Orthostatic pressure change seems to be an important determinant of diurnal pressure rhythm, while it is not a marker for the severity of hypertension.

Clinical relevance of nighttime blood pressure and of daytime blood pressure variability.

BACKGROUND: The purpose of this study was to assess whether hypertensive target organ damage is related to average nighttime blood pressure (BP) and to BP variability. METHODS: Sixty-seven normotensive subjects and 171 borderline, 309 mild, 140 moderate, and 41 severe hypertensive patients were studied with noninvasive ambulatory BP monitoring. Each subject was assigned a target organ damage score of 0 to 5 on the basis of funduscopic changes and degree of left ventricular hypertrophy calculated from electrocardiogram and chest roentgenogram. RESULTS: When the 728 subjects were subdivided into five classes of increasing daytime BP, in each class a significantly higher degree of target organ damage was present in the subjects with higher nighttime diastolic BP. A similar, although nonsignificant, trend was observed in the subjects with higher nighttime systolic BP. In particular, higher nighttime BP levels were accompanied by a more severe degree of left ventricular hypertrophy. As for variability, subjects with higher daytime systolic BP SD, but not with higher daytime diastolic SD, displayed a more severe degree of target organ damage; this was accounted for by a higher degree of retinal abnormalities. The association between target organ damage and systolic BP SD was present both in men and women, while that with nighttime BP was present only in men. No relationship was found between degree of cardiovascular complications and peaks of pressure. CONCLUSIONS: These results suggest that a reduced day-night BP difference and an increased daytime BP variability, evaluated as the SD, are associated with a higher degree of hypertensive cardiovascular complications. Whether this BP profile is the cause or the consequence of target organ damage remains to be established.

Ambulatory blood pressure monitoring in the assessment of antihypertensive treatment: 24-h blood pressure control with lacidipine once a day.

Ambulatory blood pressure monitoring gives a more representative blood pressure profile than office blood pressure measurements and is free of any placebo effect. It is therefore useful for studying the effect of antihypertensive agents. Although ambulatory blood pressure is less variable than office blood pressure, spontaneous fluctuations have been found in whole-day blood pressure when repeated measurements are taken. In the multicentre Triveneto Study, the mean difference between 24-h blood pressure recordings taken 3 months apart in 85 mild hypertensives was -0.1/-0.7 mmHg and the coefficient of repeatability (2 s.d.) was 17.3/12.6 mmHg. The corresponding values for office blood pressure were -8.7/-2.0 and 29.8/16.5 mmHg, respectively. This reduction in inter-measurement variability with ambulatory blood pressure monitoring makes it possible to reduce the sample size required to prove the effect of an antihypertensive agent in pharmacological trials. However, in the individual subject, the results of ambulatory blood pressure monitoring should be considered with caution, as 24-h blood pressure averages and profiles are subject to a degree of variability. This technique was used in 21 mild-to-moderate hypertensives to test the antihypertensive effect of lacidipine given once a day (4-6 mg) versus placebo. The drug proved effective throughout the day and night, showing a 24-h effect on blood pressure without reflex tachycardia or other intolerable side effects.

[Effect of high and low altitude exposure on the blood pressure response to physical exercise]. / Effetto dell'esposizione alle alte e basse quote sulla risposta pressoria all'esercizio fisico.

Altitude exposure is known to cause an increase in adrenergic activity, blood pressure (BP) and heart rate (HR) in resting conditions. Much less is known on the effects of the hypoxic environment on the BP and HR response to physical exercise. Five physically trained young normotensive subjects underwent a 1-hour long bicycle ergometric test to exhaustion at sea level and after 24 hours of low (1322 m) and high (3322 m) altitude exposure. HR, BP and Hb oxygen (HbO2) saturation were measured throughout the test and the recovery period. The values obtained at 60, 70, 80, 90 and 100% maximum HR were calculated. Resting BP increased by 17.9/20.9 mmHg at 3322 m (p = 0.062/0.012) and by 10.0/12.8 mmHg at 1322 m (NS). However, the BP difference present at rest gradually flattened throughout effort and at peak exercise similar BP values were obtained during the 3 tests. HbO2 saturation was lower at 3322 m compared to the other 2 settings (91.5% vs 96.7% at sea level; p less than 0.0001) and this difference progressively and remarkably increased throughout the ergometric test. At 3322 m a lower workload was reached (189 +/- 39.4 vs 240 +/- 54.8 W; p less than 0.05). In agreement with previous results these data show that exposure to both high and low altitude causes an increase in resting BP and HR; however, during strenuous exercise maximum BP and HR do not exceed the levels attained at sea level, probably on account of the lower workload that may be reached in the hypoxic environment.

[Role of ophthalmoscopy in arterial hypertension: a problem revisited]. / Ruolo dell'oftalmoscopia nell'ipertensione arteriosa: un problema rivisitato.

To evaluate the present role of fundal examination in the assessment of the hypertensive patient, 348 hypertensive subjects, mostly with borderline or mild hypertension, were studied with direct ophthalmoscopy. The exam was always performed by the same observer. The degree of left ventricular hypertrophy was also evaluated with ECG and echocardiography. Blood pressure was measured with 24-hour ambulatory monitoring, using either the Del Mar Avionics Pressurometer II and IV, the Spacelabs 5200 or the A & D TM-2420. Signs of hypertensive retinopathy were found in 51% of the subjects. The degree of retinopathy, defined according to a modified Keith-Wagener grading system, was highly correlated with average 24-hour mean blood pressure (r = 0.31; p less than 0.0001). Based on ECG, 16% of the subjects had left ventricular hypertrophy, while 23% showed an echocardiographic left ventricular mass, indexed by body surface area, above the normal limits. Left ventricular mass index was correlated with ambulatory blood pressure levels, but at a lower level of statistical significance (r = 0.19; p less than 0.001) compared to the degree of retinopathy. No correlation was found between 24-hour blood pressure and ECG findings. Ophthalmoscopy proved to be more sensitive than echocardiography and ECG in indexing 24-hour blood pressure load, while the specificity of the 3 exams was similar. The present data indicate that fundal examination is a sensitive indicator of the vascular consequences of increased blood pressure and is therefore useful in the assessment of the hypertensive patient, while the more expensive echocardiography is not of great clinical value in borderline and mild hypertension.

Haemodynamic effects of coffee and caffeine in normal volunteers: a placebo-controlled clinical study.

The acute haemodynamic effects of Italian coffee and 200 mg purified caffeine were investigated in 15 healthy non-coffee-drinkers compared to individuals who consumed placebo (highly decaffeinated coffee for regular coffee, and china bitter extract for caffeine). Before coffee and caffeine consumption and 30, 60, 90 and 120 min afterwards, rest flow and blood pressure were measured, and peripheral resistance in the arm was calculated; an echocardiogram was also performed before and 60 and 120 min after caffeine consumption. Both coffee and caffeine significantly decreased rest flow, and increased peripheral resistance. Systolic blood pressure increased by 10% and diastolic pressure increased by 5% for at least 2 h. No variation in heart rate or cardiac contractility was found. No effects were observed after placebo treatment. It is concluded that Italian coffee and caffeine increase blood pressure via vasoconstriction.

[The normal limits of arterial pressure registered with portable methods: an approach to the problem]. / Limiti di normalità della pressione arteriosa registrata con metodiche portatili: un approccio al problema.

In the present paper the problem of the normalcy limits of whole-day ambulatory blood pressure has been faced by evaluating the difference between casual and ambulatory blood pressure in a population of 522 subjects with blood pressure values covering the whole blood pressure range. On the basis of the casual blood pressure levels, 60 subjects were normotensives, 110 borderline hypertensives, 214 mild, 103 moderate and 35 severe hypertensives. The differences between casual and median 24-hour blood pressure averaged 18.4/9.6 mmHg. The difference between casual and median day-time was 14.2/6.7 mmHg. This difference was independent from the ambulatory blood pressure values and unrelated to the sex or age of subjects. The upper normal limits of ambulatory blood pressure were established by subtracting the above differences from the normal limits established by the WHO for casual blood pressure (140/90 mmHg). For 24-hour blood pressure the upper limits were 121.6/80.4 mmHg and for day-time blood pressure these were 125.8/83.3 mmHg. Contrary to previous studies conducted on normotensive populations with this approach the selection of patients based on casual blood pressure is avoided and the WHO normalcy limits are taken into account.

[Clinical significance of nocturnal blood pressure and blood pressure variability: analysis of 522 cases]. / Significato clinico della pressione notturna e della variabilità pressoria: analisi di 522 casi.

Purpose of the study was to investigate whether and to what extent blood pressure variability and average night-time blood pressure are related to cardiovascular complications in hypertension. To this aim 60 normotensive and 462 hypertensive subjects were studied by means of non-invasive 24 hour blood pressure monitoring, using either the Avionics, or the ICR Spacelabs, or the Takeda system. Each subject was attributed a target organ damage score on the basis of 12-lead electrocardiogram, chest X-ray and fundoscopy, starting from 0 (no damage) up to 5 (maximum degree of damage). The 522 subjects were subsequently subdivided into 5 classes of increasing average daytime diastolic blood pressure. In each class a higher degree of cardiovascular complications was present in the subjects with the higher blood pressure variability and the higher average night-time blood pressure. From these results it may be inferred that both blood pressure variability and night-time blood pressure are related to the degree of target organ damage in hypertension. This stresses the importance of recording blood pressure throughout the 24 hours.

Beats modulate blood pressure during running.

Blood pressure (BP) changes during running were studied in 25 subjects with intraarterial monitoring. Periodic pulse pressure variations ranging from 20 to 200 mm Hg were recorded throughout the exercise. To prove that these pressure oscillations were due to a "beat" phenomenon 10 athletes ran with a Teruflex container filled with saline: pressure changes up to +/- 62 mm Hg were recorded in the container. These pressure waves were added by computer to the sphygmic waves recorded intraarterially in the same subject during bicycle ergometry: the resultant tracing showed a beat-shaped pattern similar to that recorded during running.

[Reproducibility of ambulatory blood pressure monitoring]. / Riproducibilità della misurazione della pressione arteriosa con monitoraggio incruento.

Short-term blood pressure variability has been studied extensively with monitoring techniques. To assess whether or not and to what extent average 24-hour blood pressure varies when repeatedly recorded, 12 mild to moderate hypertensive subjects underwent 3 non-invasive blood pressure monitorings at monthly intervals. When the average 24-hour blood pressure of the whole group was evaluated no substantial differences were found between the 3 recordings, even though slightly lower blood pressure values were recorded at the first monitoring. However, when the within-period comparison was studied in the single patients, remarkable discrepancies of up to 20.9/15.8 mmHg were detected. Systolic and diastolic blood pressure variations greater than or equal to 5 mmHg were recorded in 58% of the subjects. These differences were unrelated to the number of faulty readings. Casual blood pressure varied even to a greater extent between the first and the subsequent visits; no correlation was found between casual and 24-hour blood pressure variations. The results of the present study indicate that ambulatory blood pressure may vary even to a great extent when repeatedly recorded. This finding entails important clinical implications, as the evaluation of the hypertensive patient is usually made with a single blood pressure monitoring.