Assessing circadian rhythms in propofol PK and PD during prolonged infusion in ICU patients

This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were VC = 27.7 l, VT = 801 l, and CLD = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65·(1 − 0.00714·(SBP − 135)). There was no significant circadian rhythm detected with respect to propofol pharmacokinetics. The BIS score was assessed as a direct effect model with EC50 equal 1.98 mg/l. There was no significant circadian rhythm detected within the BIS scores. We concluded that the light–dark cycle did not influence propofol pharmacokinetics and pharmacodynamics in intensive care units patients. The lack of night–day differences was also noted for systolic blood pressure, diastolic blood pressure and blood oxygenation. Circadian rhythms were detected for heart rate and body temperature, however they were severely disturbed from the pattern of healthy patients

Diurnal Variation in Urodynamics of Rat

In humans, the storage and voiding functions of the urinary bladder have a characteristic diurnal variation, with increased voiding during the day and urine storage during the night. However, in animal models, the daily functional differences in urodynamics have not been well-studied. The goal of this study was to identify key urodynamic parameters that vary between day and night. Rats were chronically instrumented with an intravesical catheter, and bladder pressure, voided volumes, and micturition frequency were measured by continuous filling cystometry during the light (inactive) or dark (active) phases of the circadian cycle. Cage activity was recorded by video during the experiment. We hypothesized that nocturnal rats entrained to a standard 12:12 light:dark cycle would show greater ambulatory activity and more frequent, smaller volume micturitions in the dark compared to the light. Rats studied during the light phase had a bladder capacity of 1.44±0.21 mL and voided every 8.2±1.2 min. Ambulatory activity was lower in the light phase, and rats slept during the recording period, awakening only to urinate. In contrast, rats studied during the dark were more active, had a lower bladder capacities (0.65±0.18 mL), and urinated more often (every 3.7±0.9 min). Average bladder pressures were not significantly different between the light and dark (13.40±2.49 and 12.19±2.85 mmHg, respectively). These results identify a day-night difference in bladder capacity and micturition frequency in chronically-instrumented nocturnal rodents that is phase-locked to the normal circadian locomotor activity rhythm of the animal. Furthermore, since it has generally been assumed that the daily hormonal regulation of renal function is a major driver of the circadian rhythm in urination, and few studies have addressed the involvement of the lower urinary tract, these results establish the bladder itself as a target for circadian regulation

Dedifferentiation and Proliferation of Mammalian Cardiomyocytes

It has long been thought that mammalian cardiomyocytes are terminally-differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle.Here we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two-thirds of which were also c-kit(+).Contradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency

Utjecaj desflurana i sevoflurana na razine oksidativnog stresa u tkivima štakora

General anaesthetics are often used in patients who are under oxidative stress due to a critical illness or surgical trauma. Some anaesthetics may worsen oxidative stress and some may act as antioxidants. The aim of this study was to evaluate liver, brain, kidney, and lung tissue oxidative stress in rats exposed to desflurane and sevoflurane and in unexposed rats. The animals were divided in three groups: control (received only air); sevoflurane (8 %), and desflurane (4 %). After four hours of exposure, we evaluated the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Cu, and Zn. Exposure to either of the anaesthetics significantly increased lung MDA levels compared to control (Mann-Whitney U test; P<0.05), probably because it is the tissue directly exposed to anaesthetic gases. Oxidative stress and antioxidant activity in other tissues varied between the desflurane and sevoflurane groups. Our results suggest that anaesthesiologist should not only be aware of the oxidative or antioxidative potential of anaesthetics they use, but should also base their choices on organs which are the most affected by their oxidative actionkisikovih radikala tako i zbog smanjene aktivnosti obrambenih sustava koji se mogu oduprijeti njihovu djelovanju. Stoga su saznanja o antioksidativnom kapacitetu anestetika koji se primjenjuju prije nekoga kirurškog zahvata vrlo važna i od velikog su kliničkog značenja. Sevofl uran i desfl uran su inhalacijski anestetici koji se učestalo rabe u svrhu uvođenja bolesnika u anesteziju. Cilj ovog istraživanja bio je utvrditi razine oksidativnog stresa u različitim tkivima štakora i usporediti razlike u odgovoru tkiva na izlaganje navedenim anesteticima. U tu svrhu razine oksidativnog stresa izmjerili smo u jetri, mozgu, bubrezima i plućima štakora podijeljenih u tri eksperimentalne skupine. Kontrolna skupina udisala je samo zrak, dok su druge dvije skupine izložene 8 %-tnomu sevofl uranu te 4 %-tnomu desfl uranu tijekom 4 h. Nakon završetka obrade životinje su žrtvovane i uzimani su im uzorci tkiva za biokemijske analize. Mjerena je razina malondialdehida (MDA), aktivnst enzima superoksid dismutaze (SOD) i glutation peroksidaze (GSH-Px) te razine bakra i cinka. Izloženost anesteticima izazvala je oksidativni stres u plućima, na što upućuje značajno povišena razina MDA (Mann-Whitney U-test P<0.05) izmjerena u plućnom tkivu štakora obiju izloženih skupina u odnosu na kontrolu. Plućno je tkivo u odnosu na ostala tkiva podložnije štetnim utjecajima reaktivnih kisikovih radikala vjerojatno stoga što je ono prvo izloženo plinovitim anesteticima nakon njihova ulaska u organizam. Razine oksidativnog stresa i antioksidativne aktivnosti koje smo izmjerili u ostalim tkivima bile su različite te su ovisile o primijenjenom anestetiku. Na osnovi dobivenih rezultata možemo zaključiti da bi se zbog različitog odgovora tkiva izbor anestetika trebao provoditi na individualnoj osnovi