Function of cGMP-dependent protein kinase II in volume load-induced diuresis

Atrial natriuretic peptide (ANP)/cGMPs cause diuresis and natriuresis. Their downstream effectors beyond cGMP remain unclear. To elucidate a probable function of cGMP-dependent protein kinase II (cGKII), we investigated renal parameters in different conditions (basal, salt diets, starving, water load) using a genetically modified mouse model (cGKII-KO), but did not detect any striking differences between WT and cGKII-KO. Thus, cGKII is proposed to play only a marginal role in the adjustment of renal concentration ability to varying salt loads without water restriction or starving conditions. When WT mice were subjected to a volume load (performed by application of a 10-mM glucose solution (3 % of BW) via feeding needle), they exhibited a potent diuresis. In contrast, urine volume was decreased significantly in cGKII-KO. We showed that AQP2 plasma membrane (PM) abundance was reduced for about 50 % in WT upon volume load, therefore, this might be a main cause for the enhanced diuresis. In contrast, cGKII-KO mice almost completely failed to decrease AQP2-PM distribution. This significant difference between both genotypes is not induced by an altered p-Ser256-AQP2 phosphorylation, as phosphorylation at this site decreases similarly in WT and KO. Furthermore, sodium excretion was lowered in cGKII-KO mice during volume load. In summary, cGKII is only involved to a minor extent in the regulation of basal renal concentration ability. By contrast, cGKII-KO mice are not able to handle an acute volume load. Our results suggest that membrane insertion of AQP2 is inhibited by cGMP/cGKII.     

Long-term efficacy of single procedure remote magnetic catheter navigation for ablation of ischemic ventricular tachycardia: a retrospective study

Long‐Term Efficacy of Single Procedure Remote Magnetic Catheter Navigation .
Background: Remote magnetic navigation (RMN) aims to reduce some inherent limitations of manual radiofrequency (RF) ablation. However, data comparing the effectiveness of both methods are scarce. This study evaluated the acute and long‐term success of RMN guided versus manual RF ablation in patients with ischemic sustained ventricular tachycardia (sVT). Methods: One hundred two consecutive patients (age 68 ± 10 years, LVEF 32 ± 12%, 88 men) with ischemic sVT were ablated with RMN (Stereotaxis; 49%) or manually (51%) using substrate and/or activation mapping (Carto) and open‐irrigated‐tip catheters. All received implantable defibrillators or loop recorders. Acute success was defined as noninducibility of any sVT at the end of the ablation procedure and long‐term success as freedom from VT upon follow‐up. Results: There was no difference in the baseline characteristics between the groups. Three patients died in hospital. Acute success rate was similar for RMN and manual ablation (82% vs 71%, P = 0.246). RMN was associated with significantly shorter fluoroscopy time (13 ± 12 minutes vs 32 ± 17 minutes, P = 0.0001) and RF time (2337.59 ± 1248.22 seconds vs 1589.95 ± 1047.42 seconds, P = 0.049), although total procedure time was similar (157 ± 40 minutes vs 148 ± 50 minutes, P = 0.42). There was a nonsignificant trend toward better long‐term success in RMN group: after a median of 13 (range 1–34) months, 63% in the RMN and 53% in the manual ablation group were free from VT recurrence (P = 0.206). Conclusion: RMN guided RF ablation of ischemic sustained VT is equally efficient compared with manual ablation in terms of acute and long‐term success rate. These results are achieved with a significantly reduced fluoroscopy time and shorter RF time. (J Cardiovasc Electrophysiol Vol. 23, pp. 499‐505, May 2012)     

Beitrag zur Kenntnis der Epithelkörperwirkung

Zusammenfassung Mit einem unter den beschriebenen Vorsichtsmaßregeln hergestellten unaufgeschlossenen EK.-Trockenpulver gelang es uns im Tierversuch, mit verhältnismäßigsehr geringen Mengen bei intramuskulärer, peroraler und rectaler Verabfolgung den Kalktiter erheblich zu steigern und bei parathyreopriven Tieren eine antitetanische Wirkung zu erzielen.Wir sind zur Zeit mit Untersuchungen über die Wirksamkeit des EK.-Trockenpulvers beim Menschen beschäftigt.     

Comparison of bioavailability and metabolism with two commercial formulations of cyclosporine a in rats.

The bioavailability and metabolism of cyclosporine A (CsA) capsules were compared with two bioequivalent (Food and Drug Administration approved) preparations in rats. Two groups of Wistar-Kyoto rats were given 10 mg/kg q.d. of Sandimmun Neoral (NEO), Novartis Pharma, and CsA (United States Pharmacopeia modified), Eon Labs (EON), as capsules dissolved in water by oral gavage. After reaching steady-state (SS), rats were euthanized 2, 4, 8, 12, and 24 h after dosing. Parallel to this investigation, a single dose (SD) study was also performed. CsA and CsA metabolite concentrations of AM1, AM4N, and AM9 were determined by high-performance liquid chromatography in kidney, whole blood, and urine. The bioavailability of EON was 15% lower [area under the curve (AUC)(SS blood CsA), 27.9 +/- 3.69 mg. h/l] in the blood and was 40% lower (AUC(SS kidney CsA), 136.2 +/- 21.2 mg. h/l) in the kidney in contrast to NEO (AUC(SS blood CsA), 32.1 +/- 4.32 mg. h/l and AUC(SS kidney CsA), 220.8 +/- 29.5 mg. h/l). In contrast, the plasma AM4N level was significantly elevated in group receiving EON (AUC(SS blood AM4N), 4.1 +/- 0.42 mg. h/l) compared with the other group treated with NEO (AUC(SS blood AM4N), 2.9 +/- 0.39 mg. h/l). In the kidneys, no significant differences were observed concerning the AM4N concentrations of NEO (AUC(SS kidney AM4N), 11.8 +/- 1.87 mg. h/l) versus EON (AUC(SS kidney AM4N), 12.1 +/- 2.14 mg. h/l), but AM1 was increased (AUC(SS kidney AM1), 54.3 +/- 11.2 mg. h/l) in comparison to NEO (AUC(SS kidney AM1), 20.5 +/- 3.56 mg. h/l). Furthermore, EON produced a larger amount of AM4N in the urine (5.8 +/- 0.85 mcirog/24 h versus 2.2 +/- 0.95 microg/24 h). Similar results were obtained with the SD study. Although the clinical consequences of our results remain at present unknown, the data suggest differences in CsA disposition that may affect drug efficacy and safety and merit further investigation in humans.     

Prenatal caffeine causes long lasting behavioral and neurochemical changes

The effects of prenatal exposure to caffeine were studied on later physical development, behavior and brain neurochemistry. Daily doses (150, 300 or 450 mg/L) of caffeine were given to rat dams during the last week of pregnancy. Prenatal caffeine exposure resulted in a number of behavioral and neurochemical changes in the offspring which were long lasting and dose related. The low dose (150 mg/L) of prenatal caffeine caused hyperactivity in an open-field. The high dose of caffeine caused learning disabilities in complex visual and auditory discrimination learning paradigms while simple motor learning or a spatial orientation task were not affected. Both male and female offspring showed some behavioral effects of caffeine exposure. The medium and high doses of caffeine resulted in weight gain that was observable as early as 35 days of age and increased progressively with age. This weight gain was associated with increased food intake. The neurochemical studies carried out at 2-3 months of age revealed an increase in choline uptake in hippocampus, mainly in the animals treated with the lower doses of caffeine and higher protein concentration (microgram/mg wet tissue) in the cortex or hippocampus of offspring exposed to the higher doses of caffeine. At 15 months of age, choline uptake in the frontal cortex was significantly reduced in the animals prenatally exposed to the 300 and 450 mg/L dose.     

Discrepant effects of unilateral and bilateral forebrain lesions on the visual performance of pigeons

The monocular and binocular performance of pigeons with bilateral, unilateral or sham lesions in the telencephalic Wulst was tested with visual discrimination tasks. Unilateral lesions yielded a marked deficit when the animals could only use the eye contralateral to the lesion. Otherwise the accomplishments of the ablated animals did not differ from that of the controls. The reciprocal inhibition of symmetrical visual brain stem centers is thought to have been unbalanced through the one-sided interruption of a known pathway descending from the Wulst.     

Can monitoring of intrathoracic impedance reduce morbidity and mortality in patients with chronic heart failure? Rationale and design of the Diagnostic Outcome Trial in Heart Failure (DOT‐HF)☆

BACKGROUND: Chronic heart failure is associated with frequent hospitalisations which are often due to volume-overload decompensation. Monitoring of intrathoracic impedance, measured from an implanted device, can detect increases in pulmonary fluid retention early and facilitate timely treatment interventions. OBJECTIVE: The DOT-HF trial is designed to investigate if ambulatory monitoring of intrathoracic impedance together with other device-based diagnostic information can reduce morbidity and mortality in patients with chronic heart failure who are treated with cardiac resynchronization therapy (CRT) and/or an implantable defibrillator (ICD). METHODS: Approximately 2400 patients will be randomised in a 1:1 fashion to a management strategy with access to the diagnostic information from the implantable device ("access arm"), or a "control arm", where this information is not made available. Study subjects fulfil standard indications for CRT and/or ICD as outlined in current guidelines. In the access arm, a fluid alert algorithm is used to give early warning of decreasing intrathoracic impedance indicating a high risk of an impending volume-overload decompensation. The primary endpoint of DOT-HF is the composite of all-cause mortality or heart failure hospitalisation. Secondary and exploratory endpoints include all-cause mortality, the impact on total health care utilization, quality of life and cost effectiveness. The study is expected to close recruitment during 2010 and to report in 2012.     

The Recombinant Bacteriophage Endolysin HY-133 Exhibits In Vitro Activity against Different African Clonal Lineages of the Staphylococcus aureus Complex,Including Staphylococcus schweitzeri

HY-133 is a recombinant bacteriophage endolysin with bactericidal activity against Staphylococcus aureus. Here, HY-133 showed in vitro activity against major African methicillin-susceptible and methicillin-resistant S. aureus lineages and ceftaroline/ceftobiprole- and borderline oxacillin-resistant isolates. HY-133 was also active against Staphylococcus schweitzeri, a recently described species of the S. aureus complex. The activity of HY-133 on the tested isolates (MIC₅₀, 0.25 μg/ml; MIC₉₀, 0.5 μg/ml; range, 0.125 to 0.5 μg/ml) was independent of the species and strain background or antibiotic resistance.     

Pharmacokinetics of levofloxacin during continuous veno-venous hemofiltration

OBJECTIVE: To study the effect of continuous veno-venous hemofiltration (CVVHF) on the pharmacokinetics of levofloxacin in critically ill patients with acute renal failure. DESIGN: Open-label study. SETTING: Anesthesiology ICU, University Hospital of Regensburg. PATIENTS: Six critically ill patients treated with CVVHF because of acute renal failure needing antimicrobial therapy. INTERVENTIONS: Levofloxacin i.v. 250 mg qd with a starting dose of 500 mg. CVVHF with the following characteristics: hemofilter AN69 hollow fibers of 0.90 m2 area, blood flow 150 ml/min, ultrafiltrate flow 1.3 l/h, filtrate substitution in post-dilution mode. MEASUREMENTS AND RESULTS: The plasma pharmacokinetics and clearance of levofloxacin by hemofiltration were established on day 1 and day 4-6 of treatment. Levofloxacin was determined by high-performance liquid chromatography (HPLC). Mean (range) peak plasma concentrations after levofloxacin 500 mg single dose (s.d.) and 250 mg multiple dose (m.d.) were 6.4 (2.7-9.4) and 8.2 (4.7-10.3) mg/l, trough levels 2.7 (1.4-5.0) and 2.9 (1.7-3.9) mg/l, half-life 28 (19-38) and 22 (17-31) h, volume of distribution 1.2 (0.72-1.6) l/kg and 0.91 (0.52-2.0) l/kg, respectively. The mean sieving coefficient was 0.96 (0.79-1.09), mean total clearance 47 (20-89) ml/min, and mean clearance by hemofiltration 21 (13-27) ml/min, respectively. CONCLUSIONS: A dosage schedule of levofloxacin 250 mg qd with a 500 mg loading dose seems appropriate for anuric patients during CVVHF. Sufficiently high steady-state concentrations of levofloxacin were achieved after the first dose. Undesired accumulation of levofloxacin was not observed.