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The Colle and Salvetti approach [Theo. Chim. Acta 37, 329 (1975)] to the calculation of the correlation energy of a system is modified in order to explicitly include into the theory the kinetic contribution to the correlation energy. This is achieved by deducing from a many electrons wave function, including the correlation effects via a Jastrow factor, an approximate expression of the one-electron reduced density matrix. Applying the latter to the homogeneous electron gas, an analytic expression of the correlation kinetic energy is derived. The total correlation energy of such a system is then deduced from its kinetic contribution inverting a standard procedure. At variance of the original Colle-Salvetti theory, the parameters entering in both the kinetic correlation and the total correlation energies are determined analytically, leading to a satisfactory agreement with the results of Perdew and Wang [Phys. Rev. B 45, 13244 (1992)]. The resulting (parameter-free) expressions give rise to a modified-local-density approximation that can be used in self-consistent density-functional calculations. We have performed such calculations for a large set of atoms and ions and we have found results for the correlation energies and for the ionization potentials which improve those of the standard local-density approximation., ((c) 2004 American Institute of Physics.)

Objectives: We sought to compare anatomic M-mode (AMM), a new echocardiographic postprocessing option, and conventional M-mode (CMM) using fundamental imaging and tissue harmonic imaging., Methods: Transthoracic echocardiography was performed in 15 selected patients to analyze the reproducibility of AMM and in 47 patients to assess its clinical value versus CMM. Acquisitions were performed successively: CMM fundamental imaging; CMM tissue harmonic imaging; tissue harmonic imaging cineloops for AMM; and fundamental imaging cineloops for AMM. Quantitative analysis was performed offline. The angle alpha between the CMM line and the septal endocardial interface was calculated and the expected percentage of error in measuring left ventricular diameter was derived., Results: AMM analysis was reproducible. Optimal AMM full echocardiographic definition was obtainable in 77% of the population, whereas CMM was optimal for 49% because of scan line misalignment, causing a measurement overestimation exceeding 5%., Conclusion: The ability with AMM to reduce the alpha angle to 0 degrees and, thus, avoid overestimation of left ventricular dimensions might improve follow-up in several pathologic conditions.

Objective: Stress hyperglycaemia increases the risk of mortality after acute myocardial infarction in diabetic and in non-diabetic patients. We aimed to determine the contribution of admission plasma glucose and HbA(1c) on post-acute myocardial infarction prognosis., Patients and Methods: Admission plasma glucose and HbA(1c) were simultaneously measured in all patients consecutively hospitalized for acute myocardial infarction. Patient survival was measured on 5 and 28 days after admission. Patients were defined as having 'previously diagnosed diabetes' (personal history of diabetes defined using ADA 1997 criteria), 'no diabetes', those without previously diagnosed diabetes and HbA(1c) below 6.5%, or 'possible diabetes', i.e. those without previously diagnosed diabetes and HbA(1c) above 6.5%., Results: Of the 146 patients included, four had died by day 5 and 14 by day 28. Admission plasma glucose was higher in patients who had died by day 28 (11.7 +/- 5.8 vs. 8.0 +/- 3.3 mmol/l, P = 0.002), whereas HbA(1c) was not (6.4 +/- 1.9 vs. 6.1 +/- 0.8%, NS). Admission plasma glucose was significantly higher in those who had died by day 28 after adjustment on HbA(1c). A multivariate analysis, including sex, age and heart failure prior to acute myocardial infarction, showed that admission plasma glucose concentration was an independent predictor of survival after acute myocardial infarction. Twenty-seven of the patients had previously diagnosed diabetes and 119 had no history of diabetes. Eleven were found to have possible diabetes. Admission plasma glucose was significantly higher in previously diagnosed diabetes (11.1 +/- 5.6) than in the other groups: 7.7 +/- 2.9 in non-diabetes, 8.2 +/- 2.1 in possible diabetes (P < 0.0001). The relationship between HbA(1c)-adjusted admission plasma glucose and mortality after acute myocardial infarction was also found in the non-diabetes group., Conclusions: Admission plasma glucose, even after adjustment on HbA(1c), is a prognostic factor associated with mortality after acute myocardial infarction. Acute rather than the chronic pre-existing glycometabolic state accounts for the prognosis after acute myocardial infarction.

A retrospective matched case-control investigation was conducted to assess risk factors suggesting Pneumocystis jiroveci pneumonia (PCP) when pneumonia occurs in adult patients with haematological malignancies. Cases and controls included were HIV-negative, presented with pneumonia and had benefited from a bronchoalveolar lavage (BAL). The presence of Pneumocystis jiroveci cysts was systematically investigated by cytochemical staining and/or immunofluorescence. Cases were patients with Pneumocystis jiroveci cysts isolated on BAL fluid (n = 31, mean age 51+/-14 y; range 20-73 y). Controls were patients without Pneumocystis jiroveci cysts (n = 62, mean age 54+/-13 y; range 25-75 y) and were matched to case patients by age and y of pneumonia diagnosis. Statistical analysis indicated that the following factors were associated with PCP: vincristine (p = 0.009, odds ratio (OR) =2.11, 95% confidence interval (CI): 1.19-3.72), a daily corticosteroid therapy for more than 1 month (p = 0.05) during the past y, and a lymphocyte count less than 0.5 x 10(9)/l on the d of pneumonia diagnosis (p = 0.04). Clinicians should be aware, in order to evoke this diagnosis when pneumonia occurs in patients with these risk factors. The goal of this exploratory study was to identify risk factors that could eventually be further investigated by a larger prospective multicentre study.

Background/aims: Retrospective studies suggest that the prognosis of patients with cirrhosis and variceal hemorrhage has improved in more recent decades. In a prospective cohort study in which the choice of prophylactic therapy was left to each practitioner, we followed cirrhotic patients with medium/large varices to determine factors predictive of bleeding and death., Methods: Three hundred fourteen patients with grades 2 or 3 esophageal varices (Child A and B/C: 218 and 96) were enrolled. One hundred seventy-three patients had no previous history of variceal bleeding. Only 245 patients (100% of patients with prior variceal hemorrhage, 61% of patients without prior hemorrhage) were receiving some form of prophylactic therapy. The median follow-up was 18 months., Results: There were 76 bleeding events and 14 related deaths (18%); nine of these deaths occurred within 24 h of bleeding onset (two at home, two during hospital transfer, and five in hospital, a mean of 2.5 h after onset; six involved Child C patients). Twenty-five deaths were not due to bleeding but were closely related to cirrhosis. In a Cox model, the presence of tense ascites (relative risk 3.4, 95% confidence interval, CI 2.5-5.9) and a prior history of hemorrhage (relative risk 4.4, 95% CI 2.6-7.5) were independent predictors of variceal hemorrhage. In patients without a prior history of bleeding, bleeding risk was higher with more prolonged prothrombin time and lower when patients were receiving propranolol., Conclusions: Despite the advent of effective drugs and endoscopic therapy for variceal bleeding, about a quarter of deaths occur very early after bleeding onset, confirming the need for rapid specific management.

Objectives: We investigated whether three platelet gene polymorphisms, Pl(A1/A2), C807T, and C-5T Kozak (encoding, respectively, for platelet membrane glycoproteins (GP) IIIa, GP Ia/IIa, GP Ibalpha), could contribute to the resistance to a low dose of aspirin (160 mg/day)., Background: Aspirin antiplatelet effect is not uniform in all patients, and the mechanism by which some patients are in vitro resistant to aspirin remains to be determined. However, it has been suggested that polymorphisms of platelet membrane glycoproteins might contribute to aspirin resistance., Methods: Ninety-eight patients on aspirin (160 mg/day) for at least one month were enrolled. Aspirin resistance was measured by the platelet function analyzer (PFA)-100 analyzer; genotyping of the three polymorphisms was performed using a polymerase chain reaction-based restriction fragment-length polymorphism analysis., Results: Using a collagen/epinephrine-coated cartridge on the PFA-100, the prevalence of aspirin resistance was 29.6% (n = 29). Aspirin-resistant patients were significantly more often Pl(A1/A1) (86.2%; n = 25) than sensitive patients (59.4%; n = 41; p = 0.01). Of the 29 patients, 25 were reevaluated after having taken 300 mg/day aspirin for at least one month. Only 11 patients still have nonprolonged collagen epinephrine closure time, and these were all Pl(A1/A1). No relation was found between resistance status and C-5T Kozak or C807T genotypes., Conclusions: Platelets homozygous for the Pl(A1) allele appear to be less sensitive to inhibitory action of low-dose aspirin. This differential sensitivity to aspirin may have potential clinical implications whereby specific antiplatelet therapy may be best tailored according to the patient's Pl(A) genotype.

This multicentre study was aimed at comparing the trough effect of telmisartan and perindopril on diastolic blood pressure (DBP), using self blood pressure measurement (SBPM). A second objective was to compare the data obtained from SBPM with those provided by automatic office BP measurement. A total of 441 mild-to-moderate hypertensive patients were randomised to receive either telmisartan 40 mg or perindopril 4 mg for a period of 12 weeks. Patients whose clinic DBP remained higher than or equal to 90 mmHg at the end of the 6th week (W6) were given a double-dose regimen. Office BP and SBPM were performed at baseline (W0), at W6 and at week 12 (W12), both with the same automatic device. A greater diminution of trough DBP was obtained with telmisartan (-6.6+/-6.7 mmHg) than with perindopril (-5.1+/-7.0 mmHg; P=0.018). Regarding clinic BP, the same results were observed. Doubling dose was significantly less frequent with telmisartan (41%; n=85) than with perindopril (55%; n=115, P=0.005). Mean values of SBPM were lower than office BP values, with a difference of a greater importance at W0 than at W12: 6.6 vs 4.7 mmHg for systolic blood pressure (P<0.005) and 3.2 vs 1.4 mmHg for DBP (P<0.0001). At W12, isolated office hypertension was found in 9% of the patients (n=37), while there were 14% of the patients (n=55) with isolated home hypertension. In conclusion, the trough effect on DBP was statistically higher with telmisartan than with perindopril. SBPM values were lower than office BP values, with greater differences before than after treatment. About a quarter of the patients were found to be controlled with a method but not with the other one.

An animal model was designed to study the chronopharmacokinetics of intravenous drugs and applied to anticancer agents vinorelbine (VNB) and methotrexate (MTX). Each experiment was performed on four pigs housed in a standardized light-dark cycle (12:12). Four pigs received a 0.16-mg bolus of VNB, followed by a 60-h continuous infusion at 0.48 mg/h. After hydration and urine alkalinization, four other pigs received a 2 mg/kg bolus of MTX, followed by two concomitant 60-h continuous infusions, one with MTX (8 mg/kg/h) and the other for hydration and folinic acid rescue (1.5 mg/kg/24 h). Serum cortisol was determined in each blood sample collected in these pigs. Blood samples were collected each hour for 60 h. The infusion flow rates and drug solution concentrations were controlled throughout the experiments. Analysis of VNB serum concentrations did not show any circadian rhythm of VNB serum concentrations. One pig administered MTX exhibited severe toxicity. Interestingly, no circadian rhythm of serum cortisol concentration was observed in this pig, whereas the three others exhibited a statistically significant cortisol circadian rhythm with a peak secretion in the morning. Two of these three pigs showed a significant 24-h rhythm of MTX with acrophase occurring at approximately 1:00 PM in both. The maximal concentration was found at 12:00 AM in the third pig. After the data were pooled, a highly significant (P < 0.01) circadian rhythm in MTX serum concentrations (57%) was found, with acrophase at midday. The pig represents a useful model for the study of chronopharmacokinetics of drugs given intravenously in human. The MTX chronokinetic variation found herein may be of interest for the improvement of chemotherapy in cancer patients.

Unlabelled: The aim of this multicentre, prospective, randomised, open study was to compare the trough effect of telmisartan (T) and perindopril (P) on diastolic blood pressure (DBP) after a 12-week treatment, using self blood pressure measurement (SBPM)., Methods: To enter the study, patients had to be 18 years of age or older and were required to suffer from mild to moderate hypertension (90 < or = PAD < 110 mmHg and/or PAS < 180 mmHg). At the end of a 3-week run-in placebo period, patients were allocated to receive either T (40 mg) or P (4 mg) once daily for a period of 12 weeks. Patients whose clinic DBP remained higher than or equal to 90 mmHg at the end of the sixth week, were given a double dose regimen. SBPM was performed over 7 consecutive days at 3 different times: at the end of the washout period (W0), at week 6 (W6) and week 12 (W12). A clinic determination of blood pressure (BP) was also performed at each visit, using the same automatic device as that used for SBPM., Results: 671 patients were selected and 441 were randomised (age: 55 +/- 12 years: 240 men and 201 women). Study populations were the following: the safety population (n = 441, T = 220; P = 221), the intent-to-treat (ITT) population (n = 435, T = 217 and P = 218), and the per protocol population (n = 368, T = 188; P = 180). ITT analysis showed a greater diminution of trough DBP from W0 to W12 with T than with P (T: -6.6 +/- 6.7 mmHg and P: -5.1 +/- 7.0 mmHg; p = 0.018 according to ANOVA for repeated measures). Regarding clinic BP, the same results were observed. Likewise, the per-protocol analysis provided similar findings. Doubling dose was significantly less frequent with T (41%; n = 85) than with P (55%; n = 115; p = 0.005). The overall frequency of adverse events was similar in both treatment groups: T = 34% (n = 74) vs p = 32% (n = 70). Most of them were of mild to moderate intensity and transient. As expected, the occurrence of cough was more frequent with P [5% (n = 12), T < 1% (n = 2), p = 0.007]., Conclusion: The trough effect on DBP was statistically higher with T (40 mg) than with P (4 mg), using SBPM as well as automatic clinic BP measurement.

Unlabelled: The aim of this study was to assess both the clinical usefulness and the economical efficiency of an in-hospital workup for patients with uncontrolled arterial hypertension., Patients and Methods: Eligible patients were hospitalized in a specialized unit between 1st January 1998 and 30th June 2000 for management of an uncontrolled arterial hypertension, to general practitioners (GPs) request. A questionnaire was sent to each of these GPs in May 2001., Results: The cohort consisted of 214 patients (107 male, 107 female, mean age: 58 +/- 16 years). Pre-hospitalisation therapy was precisely identified in 178 patients. Forty-nine patients (28%) were given more than 3 antihypertensive drugs. The most frequently administered drugs were the following: diuretics (n = 93), beta-blockers (n = 85), and ACE-inhibitors (n = 78). Mean therapy cost was 1.71 +/- 1.05 [symbol: see text]. An etiology was found in 30 patients (14%). Plasma renin was measured in 140 out of the 184 patients with essential hypertension: it was found as low (< or = 7 ng/L) in 96 patients, with 50 of them (36%) having a very low plasma renin (< or = 3 ng/L). One hundred and fifty-four questionnaires were fulfilled by the GPs. Median follow-up was 23 months. Seventeen patients were lost of follow-up. Nine cardiovascular events were listed. Mean clinic BP was < 160/95 mmHg in 86 out of the 108 patients with both an essential hypertension and a fulfilled questionnaire, including 38 patients (35%) with a clinic BP < 140/90 mmHg. Eleven patients only, were given more than 3 antihypertensive drugs. The most frequently administered drugs were: calcium antagonists (73%), followed by diuretics (50%) and beta-blockers (34%). Mean therapy cost was 1.39 +/- 0.76 [symbol: see text] (p < 0.002 vs pre-hospitalization therapy cost); 84% of the GPs answered that the in-hospital workup resulted in an useful help in managing their patients., Conclusion: The in-hospital workup of patients with uncontrolled hypertension turned out to be both clinically useful and economically efficient: an aetiology has been found in 14% of the cases; an appropriate therapy, based on the hormonal profile, allowed for a lowering of BP below 160/95 in 80% of the cases, and below 140/90 in one thirds of the patients; the mean therapy cost has been reduced by 19%.

The authors reviewed some of the most relevant studies dedicated to the assessment of the effects of the antihypertensive drugs on the stress-induced cardiovascular changes. The rises in both blood pressure and heart rate turned out not to be significantly altered by calcium channel blockers, ACE inhibitors, moxonidine, nor beta-blockers, whereas they seemed to be slightly blunted by alpha-blocking drugs. However, since baseline blood pressure was significantly lower in treated hypertensives than in placebo-given patients, all antihypertensive drugs eventually resulted in a lower blood pressure level during stress, as compared with untreated patients. Regarding white coat effect, which has to be considered as a very particular stress, it appeared to be lowered to the same extent by placebo and antihypertensive drugs; moreover, its changes were not associated with any clinical beneficial effect.

Unlabelled: THE RISK OF RESTENOSIS: Coronary angioplasty is an effective treatment of stable and instable coronary disease and its principle limitation, despite technical progress, remains restenosis. In instable angina, the physiopathologic and prognostic role of inflammation proteins is well documented. THE ROLE OF THE C-REACTIVE PROTEIN (CRP): Is a validated risk factor for patients presenting with heart failure, whether instable or stable angina and in the general population. This risk factor is distinct from tobacco abuse, hypercholesterolemia or diabetes. In all the series studied to date, the frequency of restenosis following coronary angioplasty increases when CRP values are high prior to surgery and continue to rise up to the 48th or 72nd hour., Perspectives: New therapeutic measures widen the possibilities of mechanical strategies (angioplasty with or without stent) and treatment of inflammatory mechanisms in the atheromatous plaques (statines, brachytherapy or "covered" stents).

This study was designed to analyse the relationship between the different blood pressure (BP) variabilities obtained in a non-invasive way and to determine the potential contribution of aging, severity of hypertension and increased ventricular mass to these different BP variabilities. Two hundred and six hypertensive patients underwent a 24-h ambulatory BP measurement (ABPM) as well as a photoplethysmographic BP recording and a standard echocardiography. Nocturnal BP fall and standard deviations of hourly mean BP levels as well as post-prandial fall in BP were calculated from the 24-h ABPM and were considered as indexes of long-term variability. Baroreflex sensitivity (BRS) and spectral powers of systolic BP, diastolic BP and heart rate (HR) over the low frequency band (LF: 0.05--0.14 Hz) were obtained from photoplethysmographic recording and were used as indexes of short-term variability. Short-term variability indexes were shown to be significantly related to those of long-term variability. A decrease in LF spectral powers was associated with a particular profile characterised by an attenuation of nocturnal BP fall, an increase of daytime BP standard deviations, an increase in post-prandial BP fall, a decrease in BRS and to a lesser extent, a diminution in night-time HR standard deviation. Moreover, a negative significant relationship was found between standard deviation of daytime systolic BP and both night systolic BP fall and BRS. Age and nocturnal BP level were associated with all BP variability disorders, whereas left ventricular hypertrophy was associated only with a decrease in LF spectral powers and in night BP fall, and an increase in standard deviation of daytime BP. Finally, LF spectral power of SBP was identified as independently predicted by age and night SBP fall. Journal of Human Hypertension (2001) 15, 41-48

The aim of this study was to evaluate the influence of age on the prognosis of infectious endocarditis. A retrospective study from 1987 to 1997 of 136 patients with infectious endocarditis on native, prosthetic valves or cardiac pacing catheter was performed. The outcome was analysed with the help of general practitioners. Two groups of patients were compared: 87 patients of 65 years of age or more (Group 1) and 49 patients under 65 years of age (Group 2). With a follow-up period of 5 years, the global mortality was 35%, but greater in Group 1 (p = 0.06). Cardiac failure was the main cause of death. The mortality was significantly higher in patients who were not operated (p < 0.002). The authors conclude that age of over 65 does not significantly worsen the prognosis of infectious endocarditis. The absence of surgery seems to be an indirect factor of a poor prognosis. Long-term follow-up of patients is necessary to diagnose and treat cardiac failure at an early stage and to consider referral for surgery.

Harmonic imaging is an innovative technique which is now available in most of the echographic equipment currently on the market. The use of echographic contrast agents led to the introduction of this particular technology, which has largely superseded the former method. In everyday medical practice, it seems to provide a better definition of endocardial contours. In this article, the authors have described a prospective study including 32 patients with an average age of 64 years (+/- 5 years). The aim was to compare imaging quality obtained by 2 acquisition frequencies for standard imaging with that procured by harmonic imaging (emission and reception frequency, 2.5 and 3.3 MHz respectively for the former technique; emission and reception frequency, 1.7 and 2.2 MHz respectively for the latter). The overall scores given by 2 different examiners for emission and reception frequency were as follows: 3.28 and 3.15 for 2.5 MHz, 2.84 and 2.56 for 3.3 MHz regarding the standard technique; 2.56 and 3.031 for 1.7 MHz and 2.56 and 2.063 for 2.2 MHz for the harmonic imaging technique. The superior performance of tissue harmonic imaging has been confirmed in the endocardial study of the left ventricular segments and in the analysis of the mitral valve. This study shows that harmonic imaging, a technique which was easy to use in the present study, provides a means of obtaining an average level of ultrasound imaging that facilitates the interpretation of the clinical picture.

Echocardiography does not provide objective tissue characterisation of sonified tissues. A recent advance has been the introduction of the radiofrequency signal. At present, its exploitation remains a research tool. The required material for quantification is still insufficiently robust and discriminative. The indices derived from histograms of grey scales are calculated by the majority of workers for regions of interest manually positioned in the image. This statistical method allows analysis of the average grey level but not of the architecture of the tissue examined. Tissue characterisation is, therefore, only a potential feature of echocardiography. The authors' approach consists in developing software applied to digital signal provided by the echograph and not directly by the transducer, as in the research based on the use of radiofrequency signals. This software allows characterisation of the texture by two statistical methods applied to signal processing: the histograms of the grey scales, the matrix of co-occurrence (assessing the make-up of the different grey scales in the region of interest). This tool of tissue characterisation is presented here in the studies of the interventricular septum in the parasternal long axis view. Two populations, one with healthy myocardium and the other with myocardial hypertrophy, have been studied. These two populations are differentiated in a significant manner by their respective values of parameters of myocardial texture characterisation in early diastole. Despite a number of methodological problems, this study confirms the hopes that it will be possible in the near future to obtain a quantitative "histological" definition of tissues by echocardiography.

A sensitive and very specific method, using liquid chromatography-electrospray mass spectrometry (LC-ES-MS), was developed for the determination of epirubicin, doxorubicin, daunorubicin, idarubicin and the respective active metabolites of the last three, namely doxorubicinol, daunorubicinol and idarubicinol in human serum, using aclarubicin as internal standard. Once thawed, 0.5-ml serum samples underwent an automated solid-phase extraction, using C18 Bond Elut cartridges (Varian) and a Zymark Rapid-Trace robot. After elution of the compounds with chloroform-2-propanol (4:1, v/v) and evaporation, the residue was reconstituted with a mixture of 5 mM ammonium formate buffer (pH 4.5)-acetonitrile (60:40, v/v). The chromatographic separation was performed using a Symmetry C18, 3.5 microm (150 x 1 mm I.D.) reversed-phase column, and a mixture of 5 mM ammonium formate buffer (pH 3)-acetonitrile (70:30, v/v) as mobile phase, delivered at 50 microl/min. The compounds were detected in the selected ion monitoring mode using, as quantitation ions, m/z 291 for idarubicin and idarubicinol, m/z 321 for daunorubicin and daunorubicinol, m/z 361 for epirubicin and doxorubicin, m/z 363 for doxorubicinol and m/z 812 for aclarubicin (I.S.). Extraction recovery was between 71 and 105% depending on compounds and concentration. The limit of detection was 0.5 ng/ml for daunorubicin and idarubicinol, 1 ng/ml for doxorubicin, epirubicin and idarubicin, 2 ng/ml for daunorubicinol and 2.5 ng/ml for doxorubicinol. The limit of quantitation (LOQ) was 2.5 ng/ml for doxorubicin, epirubicin and daunorubicinol, and 5 ng/ml for daunorubicin, idarubicin, doxorubicinol and idarubicinol. Linearity was verified from these LOQs up to 2000 ng/ml for the parent drugs (r > or = 0.992) and 200 ng/ml for the active metabolites (r > or = 0.985). Above LOQ, the within-day and between-day precision relative standard deviation values were all less than 15%. This assay was applied successfully to the analysis of human serum samples collected in patients administered doxorubicin or daunorubicin intravenously. This method is rapid, reliable, allows an easy sample preparation owing to the automated extraction and a high selectivity owing to MS detection.

A couple of sensitive and accurate liquid chromatography-electrospray mass spectrometry (LC- S-MS) methods for the determination of the total forms of irinotecan and its active metabolite SN-38 in human serum, using the same chromatographic and detection conditions, is presented. Both used camptothecin as internal standard (I.S.). The sample pretreatment for irinotecan involved a simple protein precipitation with acetonitrile, whereas a liquid-liquid extraction was necessary for SN-38. A Symmetry C18, 3.5 microm (150 x 1 mm I.D.) reversed-phase column was used for the chromatographic separation, together with a gradient elution of acetonitrile in 5 mM ammonium formate buffer (pH 3) as mobile phase. After ionisation in the pneumatically-assisted electrospray source and in-source collision induced dissociation, acquisition was performed in the selected ion monitoring mode. Recoveries were 69 and 47% on average, detection limits 2.5 and 0.25 ng/ml and quantitation limits 10 and 0.5 ng/ml for irinotecan and SN-38, respectively. Reproducibility was good and the method was linear from limits of quantitation up to 10,000 ng/ml for irinotecan, and up to 100 ng/ml for SN-38. This sensitive and highly specific method is suitable both for pharmacokinetic studies and routine therapeutic drug monitoring.

A wide range of definitions is used to distinguish the hypertensives with a blunted circadian pattern of blood pressure, labeled as "non dippers", from those presenting with a normal night blood pressure fall, designated as "dippers". Consequently the prevalence of non dipping phenomenon is quite uncertain: from 6 to 40% of the hypertensive subjects. The mechanisms of night blood pressure fall remain unclear, but the involvement of autonomic nervous system turns out to be partly demonstrated. From a clinical point of view, non dippers and dippers characteristics are not obviously different, but the prognosis of non dipper patients appears to be rather poor, with a more frequent target organ damage and a higher rate of cardiovascular events, as compared to dippers, even in a general population. In order to improve the identification of non dippers, an ambulatory blood pressure monitoring should be performed in patients with autonomic nervous system impairment and in subjects with target organ damage more severe than expected from office or home blood pressure measurements.

Objectives: To compare the autonomic nervous system activity indexes obtained from photoplethysmography in dipper and non-dipper hypertensive patients and to seek a potential influence of sex on the relation between autonomic nervous system and the nocturnal decrease in blood pressure., Methods: We studied 245 hypertensive patients, who underwent 24 h ambulatory blood pressure monitoring (ABPM), photoplethysmographic blood pressure recording, and echocardiography. Non-dipping patients were defined as those whose nocturnal decrease in systolic blood pressure (SBP), diastolic blood pressure (DBP), or both was less than 10% of the daytime blood pressure. Spectral powers of SBP, DBP and heart rate were obtained from photoplethysmographic recordings over three main frequency bands: very low frequency (0.005-0.05 Hz), low frequency (0.05-0.14 Hz) and high frequency (0.14-0.40 Hz)., Results: Because their ABPM were normal (less than 135/85 mmHg; n = 33), of poor quality (n = 22) or performed at a period too far from the photoplethysmographic recording (n = 17), 66 patients were excluded from the analysis. The remaining 179 patients comprised 117 dippers and 62 non-dippers. The groups did not differ regarding clinical and echocardiographic characteristics, irrespective of sex. Low-frequency spectral powers were significantly lower in non-dippers than in dippers, whatever the signal, whereas high-frequency spectral powers did not differ significantly between the groups. The nocturnal decrease in blood pressure increased with increasing low-frequency spectral powers, but was negatively correlated with high-frequency spectral powers. Multivariate linear regression analysis identified low-frequency spectral power of SBP and clinic DBP as independent factors determining the decrease in blood pressure. After adjustment for all significant covariates, the odds of being a non-dipper did not differ between men and women., Conclusion: A non-dipper profile seemed to be associated, in both men and women, with lower low-frequency spectral powers compared with those in dippers, suggesting impaired sympathetic arterial modulation.

Objective: To evaluate in a primigravid normotensive population the predictive value of outcome of the ambulatory blood pressure monitoring (ABPM) at the 4th month of pregnancy., Design and Methods: A longitudinal observational study was carried out in 174 primigravid normotensives free from proteinuria and glycosuria during the first trimester. These women underwent an ABPM (Spacelabs 90207) at 17 +/- 3 weeks gestation and were then followed up throughout pregnancy for the identification of outcome: gestational hypertension (blood pressure > or = 140/80), proteinuria, hyperuricemia, preterm delivery, birth weight < 10th percentile, need for admission to the special care neonatal unit (SCNU)., Statistics: Non parametric tests, ROC curves., Results: Of the 174 women, 170 had sufficient readings to be considered for analysis. Pre-eclampsia occurred in 5 cases (3%), gestational hypertension in 27 (16%), proteinuria in 20 (12%), hyperuricemia in 2 (1%), preterm delivery in 11 (6%), low birth weight in 9 (5%) and admission to SCNU in 16 (9%). Women with gestational hypertension already exhibited at the 4th month, both ambulatory and clinical blood pressure (BP) higher than did normotensive women (respectively: 117 +/- 7/70 +/- 5 vs 110 +/- 7/65 +/- 6 mmHg, p < 0.0001 for 24-hour ABPM, and 124 +/- 8/76 +/- 7 vs 117 +/- 10/70 +/- 9 mmHg, p < 0.005 for clinical BP). There was a non significative trend for both ambulatory and clinical values to be slightly higher in the setting of preterm delivery, proteinuria and admission to SCNU and in contrast to be slightly lower in case of low birth weight. The occurrence of one outcome or more (49 outcomes, low birth weight excepted), was associated with significantly higher ambulatory and clinical BP levels (114 +/- 7/68 +/- 6 vs 111 +/- 7/65 +/- 5 mmHg, p < 0.009 for ABPM, and 121 +/- 9/74 +/- 8 vs 117 +/- 9/70 +/- 8 mmHg, p < 0.007 for clinical BP). Positive and negative predictive values for the outcome of gestational hypertension were respectively for systolic ambulatory BP of 28% and 95% using a cut off value of 115 mmHg and for systolic clinical BP of 26% and 97% using a cut-off value of 120 mmHg., Conclusion: ABPM in a normotensive primigravid population at 17 weeks of gestation is not a better predictor of outcome, even of gestational hypertension, than clinical measurement.

Objectives: 1) To compare the autonomic nervous system activity parameters obtained from a photoplethysmographic recording in dipper and non dipper hypertensive. 2) To look for an interaction between dipper/non dipper status and gender., Methods: Prospective study involving 245 untreated hypertensives (51 +/- 13 years, 146 men, 99 women). All of the patients underwent a 24-hour ambulatory blood pressure measurement (ABPM) as well as an echocardiography for left ventricular mass index determination (LVMI) and a photoplethysmographic recording of blood pressure (BP). Nondippers were defined as those whose nocturnal decrease in systolic BP (SBP) and/or diastolic BP (DBP) was < 10% of daytime BP. Spectral powers were obtained from the photoplethysmographic recording using a fast Fourier transform over the low frequency band (LF) and the high frequency band (HF). Baroreflex sensitivity (BRS) was evaluated by the sequences method., Results: Of the 245 patients, 159 were dippers (98 men, 61 women) and 86 were non dippers (48 men and 38 women). Clinic BP was significantly higher in non dippers than in dippers (168/101 vs 161/98 mmHg; p < 0.01 for SBP and p < 0.05 for DBP) whereas daytime ABPM and LVMI were not different, whatever the gender. LF spectral powers were significantly lower in non dippers than in dippers for SBP (respectively 25 +/- 11% vs 30 +/- 13%; p < 0.01) for DBP (respectively 35 +/- 14% vs 41 +/- 15%; p < 0.01) and for HR (respectively 34 +/- 15% vs 38 +/- 15%; p = 0.03). They showed a positive correlation with the nocturnal SBP fall (r = 0.21, p < 0.001 for SBP and DBP spectral powers, r = 0.19; p < 0.005 for HR spectral power) and with the nocturnal DBP fall, too (r = 0.19; p < 0.005 for SBP spectral power, r = 0.20; p < 0.002 for DBP spectral power, r = 0.19; p < 0.005 for HR spectral power). HF spectral powers tended to be higher in non dippers than in dippers but in a non significative way. BRS was roughly the same in dippers and non dippers (7.5 +/- 2.7 vs 7.0 +/- 3.1 ms/mmHg, NS). The interaction between non dipper/dipper status and sex was non significant whatever the LF spectral power., Conclusions: 1) The greater the nocturnal BP fall, the higher the sympathetic activity indexes. 2) This relationship was found both in males and females.

A specific and sensitive method for the analysis of 24 antidepressants in human serum was developed using gas chromatography-mass spectrometry (GC/MS). This method allowed the simultaneous determination of antidepressants belonging to different classes: tricyclic antidepressants (TADs), selective serotonin reuptake inhibitors (SSRIs) and selective inhibitors of monoamine oxidase A (IMAOs). Antidepressants were submitted to liquid-liquid extraction at pH 9.5 using a mixture of heptane/isoamyl alcohol (98.5/1.5; v/v) without derivatization. Cyproheptadine was used as the internal standard (IS). Separation was obtained with a nonpolar PTE5 capillary column (30 m x 0.32 mm; film thickness 0.25 micron). Mass spectrometry consisted of electron impact ionisation (70 eV), and full scan acquisition. Extraction recoveries were over 60% for 22 antidepressants and between 35 and 95% for moclobemide and viloxazine. Limits of quantitation ranged from 20 to 100 ng/ml for most of the antidepressants, except for moclobemide and viloxazine for which it was 500 ng/ml. Intra-assay standard deviation was satisfactory. An excellent linearity was observed from the respective LOQs up to 1000 ng/ml for 22 antidepressants and up to 4000 ng/ml for moclobemide and viloxazine.

Unlabelled: The present study was designed to assess the left ventricular (LV) function by the fractional shortening (FS)/end-systolic stress (ESS) relation in untreated hypertensive patients., Methods: Two patient groups were examined: group 1 was made up of 50 patients with essential mild hypertension (44 +/- 14 years) and group 2 consisted of 16 normotensives (35 +/- 12 years). LV mass, endocardial FS, mid-wall FS and meridional ESS were measured according to the classic formulas, as well as the 24-hour ambulatory blood pressure (ABP). FS/ESS relation was analysed in hypertensive patients by 2 different ways: 1 degree graphically, with the 95% confidence interval of the normal FS/ESS relation as a reference: 2 degrees statistically, by comparing the observed FS values with those FS value expected from ESS, using equations derived from normal subjects (McMemar chi 2 test, or binomial rule)., Results: The graphic examination allowed for the identification of a depressed, normal or increased LV function in, respectively, 7, 31 and 12 patients, using the endocardial FS/ESS relation, against 30, 18 and 2 patients, using the mid-wall FS/ESS relation. Likewise, the statistical analysis of the differences between the observed FS values and the expected FS values showed 13 discrepancies, all of them being related to an overestimation of the LV function, an assessed by the endocardial FS/ESS relation (p < 0.01). Such a trend turned out to be more significant in patients with an increased ABP (n = 31; p < 0.05) than in "white coat" hypertensives (n = 9; p < 0.08): in contrast, it was of the same extent in patients with an increased LV mass (n = 17; p < 0.05) as in those with a normal LV mass (n = 33; p < 0.05)., Conclusions: 1/After adjustment for ESS, mid-wall FS (a direct measure of myocardial fiber shortening) was more often decreased than endocardial FS (reflecting chamber dynamics). 2/Mid-wall FS was also found to be a better tool for assessing LV function in patients with normal LV mass, and, to a lesser extent, in "white coat" hypertensives.

Baroreflex sensitivity (BRS) is altered in a variety of circumstances and could be considered as a marker for the prognosis of some cardiovascular diseases. The present study was designed to evaluate the reproducibility of noninvasive measures of BRS, both at mid- and at long-term. Fourteen healthy volunteers were examined on three occasions (first interval = 1 week, second interval = 1 year). Each recording was performed using a noninvasive photoplethysmographic device (Finapres 2300, Ohmeda), both in supine and standing positions. Two different methods of measurement were used: the sequences method and cross spectral analysis. The reproducibility of BRS measures was as satisfactory at mid- as at long-term for the sequences method (intraclass coefficient [ICC] = 0.87 and 0.86, respectively), but it was better at mid- than at long-term for the cross-spectral analysis (ICC = 0.85 and 0.54, respectively). The measures performed in standing position were obviously more reproducible than those made in recumbent position (ICC = 0.87 and 0.70 for the sequences method, 0.85 and 0.71 for the cross-spectral analysis, respectively). Due to the high reproducibility of these noninvasive measures, the number of patients to be included in a pharmacological study was calculated as rather small: for example, only 20 patients are required for detecting a change in upright BRS of 3 msec/mm Hg, at long-term (sequences method). Likewise, the magnitude of the regression to the mean, which has to be expected in patients selected for a follow-up study, turned out to be low: for example, <15% of the difference between the patient group mean value and the reference value, both at mid- and at long-term (standing position, sequences method). We conclude that: 1) The noninvasive measures of BRS in standing position are reproducible enough to allow longitudinal studies to be conducted over either a short or a long period; 2) The long-term reliability of the sequences method seems to be higher than that of the cross-spectral analysis; and 3) Subtle changes in SBR may be noninvasively detected within small patient groups.

Purpose: To assess the diagnostic value of the recovery phase patterns of the ST-segment depression in patients referred for chest pain., Patients and Methods: Continuous plots of ST-segment depression against heart rate during exercise and recovery were constructed within a population of 160 consecutive symptomatic patients who all had undergone catheterization (80 with > or = 1 stenosis > or = 50%). We used a new quantitative method of measurement allowing all kinds of rate recovery loops (even the so-called "intermediate" loops) to be considered for analysis. The measurements of the heart rate (HR)-adjusted ST-segment depression were performed at 20 and 60 ms from the J point, providing two different values of a quantified recovery loop index (RLI): RLI 20 and RLI 60., Results: Both RLI showed a higher specificity (0.81 +/- 0.04 and 0.74 +/- 0.05, respectively) than did the standard criterion (0.65 +/- 0.10), but the difference was significant regarding RLI 20 only (P = 0.011). As to the sensitivity, no significant differences were found among all of the criteria (0.74 +/- 0.05, 0.80 +/- 0.04, 0.76 +/- 0.05, respectively). The timing of measurements of the RLI within the repolarization phase did not affect their overall accuracy (0.77 +/- 0.03 for both RLI). The values of the receiver-operating characteristic (ROC) curve areas were significantly greater for both RLI (0.83 +/- 0.06 and 0.84 +/- 0.06 respectively) than for the standard criterion (0.75 +/- 0.07; P < 0.02). Finally, both RLI allowed to differentiate accurately the study subjects according to the number of diseased vessels, whereas the standard criterion could only distinguish between CAD patients and subjects with normal angiograms., Conclusion: The quantitative analysis of the rate recovery phase patterns appears to be useful for the diagnosis of coronary heart disease and the assessment of its severity in symptomatic patients.

Aim of the Study: To compare heart rate (HR) and blood pressure (BP) variability in hypertensive patients with or without a fall in BP during the night., Methods: 33 mild to moderato hypertensive patients, mean age 45 +/- 15 years, underwent an echocardiogram, a 24-hr ambultory BP monitoring (ABPM), and a 24-hr ECG monitoring. In addition, a continuous BP recording over 15 minutes was performed between 9 and 11 a.m. both in supine and standing positions, by using digital plethysmography (Finapres device)., Statistical Analysis: non parametric tests., Results: [table: see text], Conclusion: In non dippers, morning BP and HR low-frequency oscillations are shifted to a lower level, as compared to dippers. This characteristic is associated with a reversed circadian pattern of sympathetic activity.

Aim of the Study: to assess the reproducibility of blood pressure and heart rate variability measurements in time and frequency domain, by using a Finapres device in healthy volunteers., Methods: 16 normotensive subjects aged 22 to 51 years underwent within a 5-day interval two non-invasive blood pressure recordings by a Finapres device over 15 minutes both in supine and standing positions, at the same time of the day., Statistical Analysis: non parametric tests, relative errors, and intraclass correlation coefficient., Results: [table: see text], Conclusion: the data provided by the FINAPRES device, especially the baroreflex sensitivity measured in standing position, show a good day to day reproducibility.

Aim of the Study: To compare heart rate (HR) and blood pressure (BP) variability in hypertensives with or without left ventricular hypertrophy (LVH)., Methods: Thirty-three mild to moderate hypertensive patients, mean age 45 +/- 15 years, underwent an echocardiogram, a 24 hr ambulatory BP monitoring (ABPM), a 24 hr ECG monitoring and a continuous BP recording over 15 minutes both in supine and standing positions, by using digital plethysmography (Finapres device)., Statistical Analysis: non parametric tests., Results: [table: see text], Conclusion: LVH is associated with a reduction in the markers of sympathetic activity and a decreased baroreflex sensitivity.

The main advantages of ambulatory blood pressure monitoring (ABPM) over clinic blood pressure measurements are the following: the lack of an alarm reaction and of observer bias; repeated readings during 24 h in the customary environment of the patient, instead of a single measurement in the doctor's office; superior reproducibility, allowing the sample size of study groups to be reduced substantially; and multiple data, likely to be analysed by several complementary methods. The different non-pharmacological interventions could be classified as follows: probably ineffective (sodium intake restriction, caffeine intake restriction, abstinence from alcohol consumption), probably effective (potassium supplementation, magnesium supplementation, weight reduction by overweight patients, cessation of smoking) and requiring further investigation (psychological interventions, physical activity, dietary lipid level modifications). The effects of pharmacological treatment may be accurately assessed by using ABPM: detailed information is given concerning the duration of action of the antihypertensive drugs; different regimens of the same treatment mayi be compared with each other or with placebo; and the trough: peak ratio can be determined for each drug. It is noteworthy that all of these subtle measurements have to be performed in patients the blood pressure of whom seems to respond adequately to the drug under evaluation. An additional key role for ABPM in clinical trials could be to establish selection criteria both for trial entry and for dose adjustment.

We retrospectively studied 216 mild to moderate hypertensive patients receiving either an angiotensin converting enzyme inhibitor (ACEI) or a calcium antagonist (CA), as a once-a-day monotherapy; their blood pressure had been measured using both a sphygmomanometer and an ambulatory blood pressure recorder. Numerous discrepancies were found between the two methods of blood pressure measurement with respect to systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as pulse pressure (PP). Clinic blood pressure measurement did not show any significant differences between the effects of ACEI and those of CA, whereas ambulatory blood pressure measurements (ABPM) showed that in patients with normal ambulatory blood pressure (so-called 'white coat' hypertensive patients), ACEI only (but not CA) significantly lowered SBP, DBP and PP. Accordingly, a threshold of efficacy was sought: it appeared to be lower for ACEI than for CA (120/80 vs 140/85 mmHg). Furthermore, for a given degree of DBP lowering, SBP and PP were more lowered by ACEI than by CA, indicating a greater effect of ACEI on arterial compliance. Likewise, for a given level of mean blood pressure, SBP and PP were lower and DBP slightly higher in patients on ACEI than in those on CA. Our data are consistent with some recent papers, emphasizing a heightened activity of the renin-angiotensin system in 'white coat' hypertensive patients.

The selection of a group of patients based on a high value of a clinical or biological parameter leads to the finding of a tendency to a reduction of this value when remeasured, known as "regression towards the mean". The amplitude of this phenomenon is greater when the selected subjects are far from normal values and the intra-individual variability of the parameter under consideration is very high. Measurement of left ventricular mass is very affected by this statistical phenomenon. The authors undertook a prospective study to analyse the components of variability of repeated echocardiographic measurements of left ventricular mass and to quantify the expected effect of regression towards the mean in the follow-up of patients with left ventricular hypertrophy. Twenty-five randomly chosen subjects underwent 2 echocardiographic examinations at 2 week intervals: at each visit, the patient had two recordings and each recording was measured twice by the same "blinded" operator. Variance analysis showed intra-individual variability represented 30% of total variability, comprising only 2% for the measurements and 28% for the recordings and the visits. The importance of regression towards the mean was calculated with respect to the initial value of the left ventricular mass index: for example, when the left ventricular mass index was 150 g/m2, a spontaneous regression of 18 g/m2 can be expected at the next measurement. This phenomenon should be taken into consideration in the interpretation of longitudinal echocardiographic studies.

Unlabelled: Hypertensive patients complaining of chest pain often have a normal coronary angiogram despite a pathological exercise tolerance test. The aim of the present study was to establish whether the prevalence of these "false-positive" tests could be lowered by adjusting ST segment depression for exercise-induced increase in heart rate., Methods: 60 hypertensive patients, mean age 59 years, with typical or atypical chest pain, underwent both a symptom-limited exercise test and a coronary angiogram within a median period of 1 day. The ST segment depression was measured every 20 ms from the J point. A stepwise discriminant analysis was performed: a canonical variable took into account the Detrano index, the quantified rate-recovery loop index (QRL index) as well as the presence of a LV hypertrophy (Romhilt Estes Score)., Results: [table: see text], Conclusion: in hypertensive patients with chest pain, the specificity and the positive predictive value of exercise test are significantly improved by adjusting ST segment depression for heart rate both during effort and recovery and by taking into account the score of Romhilt Estes on the baseline ECG recording.

The high degree of the intra-individual variability of blood pressure (BP) is related both to biological and technological factors: the biological components of variability are either linked to sympathetic system and respiratory movements or induced by physical and psycho-sensorial stresses; the technological sources of variability are the apparatus and the doctor. The consequences of this high variability can be quantified: the risk for a between-visit change of 35 mmHg for systolic BP (and 17 mmHg for diastolic BP) to be due to the spontaneous BP variability, is as high as 95%. Moreover, according to the regression to the mean, in selected patients with a mean SBP as high as 160 mmHg, a mean spontaneous decrease of 9 mmHg is expected to occur, at the next visit. The physician has then to manage the lack of accuracy of clinic BP measurements. For this purpose, three strategies have to be used: thoroughly examining the patient (if associated with an organ damage, the high BP undoubtedly requires to be treated); rigorously taking into account the published recommendations of BP measurements (the sources of error are now well known and may be easily corrected); finally, using the most sophisticated methods of BP measurements (elf BP measurement), semi-ambulatory or ambulatory BP monitoring, exercise testing), which in some circumstances, may provide useful additional information.