Loukia Zerva

Cognitive Impairment Is Related to Increased Arterial Stiffness and Microvascular Damage in Patients With Never-Treated Essential Hypertension

BACKGROUND It is known that essential hypertension may be implicated in the development of cognitive impairment that is associated to microvascular disease of the brain. It has been hypothesized that increased arterial stiffness of the large arteries may lead to microvascular changes due to increased pulsatile flow. Our study tests the hypothesis that large artery stiffness and microvascular damage are related to brain microcirculation changes as reflected by impaired cognitive function. METHODS We studied 110 nondiabetic patients aged 40-80 years (mean age 53.8 +/- 11.2 years, 57 men) with recently diagnosed stage I-II essential hypertension. Mini-Mental State Examination (MMSE) was used as a screening test for global cognitive impairment. We performed both 2-D echocardiography and carotid-femoral pulse wave velocity (PWV) in order to evaluate arterial stiffness. Twenty-four hour urine microalbumin excretion was measured as a marker of microvascular damage. RESULTS In the entire population, MMSE was negatively correlated with age (r = -0.42, P < 0.001), 24-h pulse pressure (PP) (r = -0.18, P < 0.05), and PWV (r = -0.3, P = 0.003). Additionally, MMSE was not independently correlated with microalbuminuria in patients aged over 65 years (r = -0.58, P = 0.003). CONCLUSIONS Impaired cognitive function is associated with increased large artery stiffness and microalbumin excretion in newly diagnosed, untreated hypertensive patients. These findings support the hypothesis that cognitive impairment induced by impaired microcirculation is linked to large artery stiffness and microvascular damage.

Comparative Evaluation of Three Commercial Identification Systems Using Common and Rare Bloodstream Yeast Isolates

ABSTRACT The commercial yeast identification systems API ID32C, Auxacolor, and Vitek were evaluated using 251 molecularly identified bloodstream isolates and 2 reference strains, representing a total of 35 species (6 common and 29 rare). Correct identification rates were higher for common species (Auxacolor, 95%; API ID32C, 94%; Vitek, 92%) than for rare species (Auxacolor, 43%; API ID32C, 56%; Vitek, 64%). All systems performed equally among the former, and Vitek performed best among the latter.

Association of Target Organ Damage With Three Arterial Stiffness Indexes According to Blood Pressure Dipping Status in Untreated Hypertensive Patients

BACKGROUND Subclinical organ damage represents an intermediate stage in the continuum of vascular disease and a determinant of overall cardiovascular risk. We investigated the associations of pulse wave velocity (PWV), ambulatory arterial stiffness index (AASI), and office pulse pressure (PP) with several target organ damages (TODs) in newly diagnosed and never-treated patients with essential hypertension with respect to their dipping profile. METHODS One hundred sixty-eight hypertensive patients with recently diagnosed and never-treated stage I-II essential hypertension were evaluated with respect to the relationship of PWV, AASI, and office PP with TOD including microalbumin (MAU) levels, cognitive function, intima-media thickness (IMT), coronary flow reserve (CFR), left ventricular mass (LVM), left ventricular filling pressures, diastolic dysfunction, and left atrium (LA) enlargement. RESULTS Simultaneous estimation of AASI, PWV, and office PP independently associated with the following: (i) CFR (P < 0.01), 24-h urine albumin excretion rates (P < 0.05), left ventricular diastolic dysfunction (P < 0.01), and LA enlargement (P < 0.01) in never-treated hypertensive patients; (ii) CFR (P < 0.05), IMT (P < 0.01), left ventricular diastolic dysfunction (P < 0.05), and LA enlargement (P < 0.05) in dippers; and (iii) CFR (P < 0.05) and LA enlargement (P < 0.01) in nondippers. Nonindependent relationships revealed between (i) AASI and left ventricular filling pressures and (ii) PWV and cognitive dysfunction in never-treated hypertensive patients. CONCLUSIONS The simultaneous estimation of three noninvasive indexes of arterial stiffness leads to valuable information regarding their association with TOD including CFR, MAU levels, IMT, left ventricular diastolic dysfunction, and LA enlargement in never-treated hypertensive patients regarding their dipping status.

Pharmacodynamic effects of simulated standard doses of antifungal drugs against Aspergillus species in a new in vitro pharmacokinetic/pharmacodynamic model

ABSTRACT In conventional ΜΙC tests, fungi are exposed to constant drug concentrations, whereas in vivo, fungi are exposed to changing drug concentrations. Therefore, we developed a new in vitro pharmacokinetic/pharmacodynamic model where human plasma pharmacokinetics of standard doses of 1 mg/kg amphotericin B, 4 mg/kg voriconazole, and 1 mg/kg caspofungin were simulated and their pharmacodynamic characteristics were determined against three clinical isolates of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus with identical MICs (1 mg/liter for amphotericin B, 0.5 mg/liter for voriconazole) and minimum effective concentrations (0.5 mg/liter for caspofungin). This new model consists of an internal compartment (a 10-ml dialysis tube made out of a semipermeable cellulose membrane allowing the free diffusion of antifungals but not galactomannan) inoculated with Aspergillus conidia and placed inside an external compartment (a 700-ml glass beaker) whose content is diluted after the addition of antifungal drugs by a peristaltic pump at the same rate as the clearance of the antifungal drugs in human plasma. Fungal growth was assessed by galactomannan production. Despite demonstrating the same MICs, amphotericin B completely inhibited (100%) A. fumigatus but not A. flavus and A. terreus, whose growth was delayed for 7.53 and 22.8 h, respectively. Voriconazole partially inhibited A. fumigatus (49.5%) and Α. flavus (27.9%) but not Α. terreus; it delayed their growth by 3.99 h (A. fumigatus) and 5.37 h (Α. terreus). Caspofungin did not alter galactomannan production in all of the species but A. terreus. The new model simulated human pharmacokinetics of antifungal drugs and revealed important pharmacodynamic differences in their activity.

Polyphasic Identification and Susceptibility to Seven Antifungals of 102 Aspergillus Isolates Recovered from Immunocompromised Hosts in Greece

ABSTRACT In this study, the first such study in Greece, we used polyphasic identification combined with antifungal susceptibility study to analyze Aspergillus clinical isolates comprising 102 common and rare members of sections Fumigati, Flavi, Terrei, Nidulantes, Nigri, Circumdati, Versicolores, and Usti. High amphotericin B MICs (>2 μg/ml) were found for 17.6% of strains. Itraconazole, posaconazole, and voriconazole MICs of >4 μg/ml were shown in 1%, 5%, and 0% of the isolates, respectively. Anidulafungin, micafungin, and caspofungin minimum effective concentrations (MECs) of ≥2 μg/ml were correspondingly recorded for 4%, 9%, and 33%, respectively, of the strains.

Ruling out Bacillus anthracis.

Optimization of methods for ruling out Bacillus anthracis leads to increased yields, faster turnaround times, and a lighter workload. We used 72 environmental non–B. anthracis bacilli to validate methods for ruling out B. anthracis. Most effective were horse blood agar, motility testing after a 2-h incubation in trypticase soy broth, and screening with a B. anthracis–selective agar.

Amphotericin B- and Voriconazole-Echinocandin Combinations against Aspergillus spp.: Effect of Serum on Inhibitory and Fungicidal Interactions

ABSTRACT Antifungal combination therapy with voriconazole or amphotericin B and an echinocandin is often employed as primary or salvage therapy for management particularly of refractory aspergillosis. The pharmacodynamic interactions of amphotericin B- and voriconazole-based combinations with the three echinocandins caspofungin, micafungin, and anidulafungin in the presence of serum were tested against 15 Aspergillus fumigatus complex, A. flavus complex, and A. terreus complex isolates to assess both their growth-inhibitory and fungicidal activities. The in vitro activity of each drug alone and in combination at a 1:1 fixed concentration ratio was tested with a broth microdilution colorimetric method, and interactions were assessed by isobolographic analysis. Synergy was found for all amphotericin B- and voriconazole-based combinations, with amphotericin B-based combinations showing strong inhibitory synergistic interactions (interaction indices of 0.20 to 0.52) and with voriconazole-based combinations demonstrating strong fungicidal synergistic interactions (interaction indices of 0.10 to 0.29) (P < 0.001). Drug- and species-specific differences were found, with caspofungin and the A. fumigatus complex exhibiting the weakest synergistic interactions. In the presence of serum, the synergistic interactions were reduced in the order (from largest to smallest decrease) micafungin > anidulafungin > caspofungin, and A. flavus complex > A. fumigatus complex > A. terreus complex, resulting in additive interactions, particularly for inhibitory activities of amphotericin B-echinocandin combinations and fungicidal activities of voriconazole-echinocandin combinations. Drug- and species-specific differences were found in the presence of serum for inhibitory activities of antifungal drugs, with the lowest interaction indices being observed for amphotericin B-caspofungin (median, 0.77) and for the A. terreus complex (median, 0.56). The present in vitro data showed that serum had a major impact on synergistic interactions of amphotericin B-echinocandin and voriconazole-echinocandin combinations, resulting in additive interactions and explaining the indifferent outcomes usually observed in vivo.

Association of the dopamine D3 receptor Ser9Gly and of the serotonin 2C receptor gene polymorphisms with tardive dyskinesia in Greeks with chronic schizophrenic disorder.

Association of the dopamine D3 receptor Ser9Gly and of the serotonin 2C receptor gene polymorphisms with tardive dyskinesia in Greeks with chronic schizophrenic disorder Emmanouil N. Rizos, Nikolaos Siafakas, Eleni Katsantoni, Vassiliki Lazou, Konstantinos Sakellaropoulos, Anastasia Kastania, Sophia Kossida, Kalliopi-Stavroula Chatzigeorgiou, Georgios Arsenis, Loukia Zerva, Konstantinos Katsafouros and Lefteris Lykouras

Inhibitory and Fungicidal Effects of Antifungal Drugs against Aspergillus Species in the Presence of Serum

ABSTRACT Given the high protein binding rates of antifungal drugs and the effect of serum proteins on Aspergillus growth, we investigated the in vitro pharmacodynamics of amphotericin B, voriconazole, and three echinocandins in the presence of human serum, assessing both inhibitory and fungicidal effects. In vitro inhibitory (IC) and fungicidal (FC) concentrations against 5 isolates of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus were determined with a CLSI M38-A2-based microdilution method using the XTT methodology after 48 h of incubation at 35°C with a medium supplemented with 50% human serum. In the presence of serum, the IC and FC of amphotericin B and the IC of echinocandins were increased (1.21- to 13.44-fold), whereas voriconazole IC and FC were decreased (0.22- to 0.90-fold). The amphotericin B and voriconazole FC/IC ratios did not change significantly (0.59- to 2.33-fold) in the presence of serum, indicating that the FC increase was due to the IC increase. At echinocandin concentrations above the minimum effective concentration (MEC), fungal growth was reduced by 10 to 50% in the presence of human serum, resulting in complete inhibition of growth for some isolates. Thus, the in vitro activities of amphotericin B and echinocandins were reduced, whereas that of voriconazole was enhanced, in the presence of serum. These changes could not be predicted by the percentage of protein binding, indicating that other factors and/or secondary mechanisms may account for the observed in vitro activities of antifungal drugs against Aspergillus species in the presence of serum.

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a New In Vitro Dynamic Model

ABSTRACT The pharmacodynamics (PD) of voriconazole activity against Aspergillus spp. were studied using a new in vitro dynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. Three Aspergillus clinical isolates (1 A. fumigatus, 1 A. flavus, and 1 A. terreus isolate) with CLSI MICs of 0.5 mg/liter were tested in an in vitro model simulating voriconazole PK in human plasma with Cmax values of 7, 3.5, and 1.75 mg/liter and a t1/2 of 6 h. The area under the galactomannan index-time curve (AUCGI) was used as the PD parameter. In vitro PK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. The in vitro PK-PD relationship of fAUC0-24-AUCGI followed a sigmoid pattern (global R2 = 0.97), with near-maximum activities (10% fungal growth) observed at an fAUC0-24 (95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter against A. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter against A. flavus, and 36.2 (27.8 to 45.7) mg · h/liter against A. terreus (F test; P < 0.0001). Target attainment for 3, 4, and 5 mg/kg-of-body-weight voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) for A. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) for A. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) for A. terreus. Based on the in vitro exposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients with A. fumigatus but not A. flavus and A. terreus infections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage.