A-22) and 2004 (Fourteenth European Congress of Clinical Microbiology and Infectious Diseases, Abstract 902) and tigecycline has not been studied for UTI treatment besides case series. 3 A follow-up letter suggested that use of a higher than recommended dose may be effective for MDR Klebsiella pneumoniae or Acinetobacter baumannii urosepsis. 4 Moreover, the author provided 'estimates' of serum and urinary concentrations following 100, 200 and 400 mg loading doses, and 50 mg every 12 h, 100 mg every 12 h and 200 mg every 24 h maintenance doses, respectively. 3,4 Urine concentration was assumed to be 0.3, 0.6 or 1.2 mg/L depending on the dosing schedule at an unstated time post-dose based on a serum concentration of 1.5, 3.0 or 6.0 mg/L, respectively. 4 A linear relationship between dose and plasma/urine concentration was assumed and urine concentrations were calculated to be 20% of serum concentrations. Neither of these claims has a pharmacokinetic basis or considered varying dosing intervals. The assumption of linearity also contradicted a statement made in the letter about tigecycline kinetics resembling doxycycline's concentration-dependent kinetics at high doses. 4 If one accepts that 15%-22% of tigecycline is excreted unchanged in the urine with standard dosing of 50 mg every 12 h, then the amount excreted would be 100 mg/dayÂ0.15-0.22 (i.e. 15-22 mg/day). Typical urine output is generally ,2 L/day; thus, urinary concentrations should average 7.5-11 mg/L or greater. In a clinical pharmacology review, 14.8% of a 50 mg dose was claimed to be excreted as tigecycline epimer and 2.0% was claimed to be excreted as unchanged drug. 5 The tigecycline epimer was described as pharmacologically inactive. However, tracing these data to the original published report revealed that the percentages were reversed. 6 Unchanged tigecycline urine excretion of 14.8% rather than 2.0% is consistent with the low-end percentage excreted range reported in the literature. Average tigecycline urine concentrations are expected to exceed the MIC for Gram-negative isolates reported as susceptible by several-fold; however, there is concern over whether serum concentrations would also exceed the MIC in bacteraemic patients. Nothing has been published about the activity of tigecycline in urine and the extent that activity depends on urine pH or metal cation concentrations. Tigecycline should not be used for UTI when other therapies including aminoglycosides, carbapenems and colistin are options; however, in rare situations, tigecycline may be considered. Current data do not support the need for or safety of high-dose tigecycline as suggested by Cunha et al. 3 and Cunha. 4

SummaryWe investigated the PKC-mediated phosphorylation of paxillin within its LIM4 domain and the involvement of this phosphorylation in activation of LFA-1 integrins of the Baf3 pro-B lymphocytic cell line. Using phosphorylated-threonine-specific antibodies, phosphorylated amino acid analysis and paxillin phosphorylation mutants, we demonstrated that TPA, the pharmacological analog of the endogenous second messenger diacyl glycerol, stimulates paxillin phosphorylation at threonine 538 (T538). The TPA-responsive PKC isoform PKC directly binds paxillin in a yeast two-hybrid assay and phosphorylates paxillin at T538 in vitro and also coimmunoprecipitates with paxillin and mediates phosphorylation of this residue in vivo. Recombinant wild-type paxillin, its phosphoinhibitory T538A or phospho-mimetic T538E mutants were expressed in the cells simultaneously with siRNA silencing of the endogenous paxillin. These experiments suggest that phosphorylation of paxillin T538 contributes to dissolution of the actin cytoskeleton, redistribution of LFA-1 integrins and an increase in their affinity. We also show that phosphorylation of T538 is involved in the activation of LFA-1 integrins by TPA.

BackgroundLevetiracetam is a frequently used drug in the therapy of partial onset, myoclonic and generalized tonic-clonic seizures. The main route of elimination is via the kidneys, which eliminate 66% of the unchanged drug as well as 24% as inactive metabolite that stems from enzymatic hydrolysis. Therefore dose adjustments are needed in patients with chronic kidney disease stage 5 D, i.e. patients undergoing dialysis treatment. In this patient population a dose reduction by 50% is recommended, so that patients receive 250–750 mg every 12 hours. However “dialysis” can be performed in using different modalities and treatment intensities. For most of the drugs pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis are not available. This is the first report on levetiracetam pharmacokinetics in a peritoneal dialysis patient.Case presentationA 73-y-old Caucasian male (height: 160 cm, weight 93 kg, BMI 36.3 kg/m2) was admitted with a Glasgow Coma Scale of 10. Due to diabetic and hypertensive nephropathy he was undergoing peritoneal dialysis for two years. Eight weeks prior he was put on levetiracetam 500 mg twice daily for suspected partial seizures with secondary generalization. According to the patient’s wife, levetiracetam lead to fatigue and somnolence leading to trauma with fracture of the metatarsal bone. Indeed, even 24 hours after discontinuation of levetiracetam blood level was still 29.8 mg/l (therapeutic range: 12 – 46 mg/l). Fatigue and stupor had disappeared five days after discontinuation of the levetiracepam. A single dose pharamockinetic after re-exposure showed an increased half life of 18.4 hours (normal half life 7 hours) and levetiracetam content in the peritoneal dialysate. Both half-life and dialysate content might help to guide dosing in this patient population.ConclusionIf levetiracetam is used in peritoneal dialysis patients it should be regularly monitored to avoid supratherapeutic levels that could lead to severe sequelae.

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Therapie von Narben und FaltenEs steht eine Vielzahl von therapeutischen Alternativen zur Verfügung, um ästhe-tisch störende Hautveränderungen, insbesondere Falten und Narben, zu behandeln. Im Fall von Falten, Photoaging oder Striae distensae gelten chemische Peelings und ablative Methoden, wie Laserresurfacing und Dermabrasion, als Mittel der Wahl. Bei flächigen und linearen Narben hingegen kommen überwiegend chirurgische Verfahren, u. a. Exzisionen, auch seriell, Expander oder Hauttransplantationen zum Einsatz (. Tab. 1,[17,20]). Der Effekt der sogenannten ablativen Verfahren wird durch eine Schädi-gung oder Zerstörung der Epidermis und der Basalmembran der Haut hervorgerufen. Die Verletzung kann bei falscher Anwendung bis in die papilläre Dermis reichen und führt auf diese Weise zu einer Deepithelialisierung. Es entsteht eine oberflächliche Wunde, durch welche die inflammatorische Wundheilungskaskade aktiviert wird. Nacheinander, aber auch überlappend, werden eine Exsudations-, eine Granulations-und eine Epithelialisierungsphase durchlaufen. Die Exsudationsphase entspricht einer initialen Entzündungsphase, in welcher die inflammatorische Kaskade mit Bildung einer Vielzahl von Wachstumsfaktoren und proinflammatorischen Zytokinen aktiviert wird, wodurch schließlich die Fibroblasten stimuliert werden [12, 18]. Die Granulationsphase ist eine Proliferationsphase mit Bildung eines Narben gewebes anstelle einer normalen Kollagen-Elastin-Matrix durch die aktivierten Fibroblasten [22]. Durch die hieraus resultierende Fibrose in der papillären Dermis kommt es zur Hautstraffung oder Faltenglättung. » Nach dermabrasiven Verfahren ist die regenerierte Epidermis oft ausgedünnt Histologisch betrachtet sind nach diesen dermabrasiven Verfahren in vielen Fällen die regenerierte Epidermis ausgedünnt und die dermalen Papillen abgeflacht. Dies entspricht nicht mehr dem physiologischen Hautbild. Die Haut wird anfäl-liger gegenüber UV-Schäden und es besteht -gerade bei dunkleren Hauttypenzusätzlich eine erhöhte Gefahr postoperativer Pigmentverschiebungen [23].Außerdem wird durch die Deepithelialisierung eine Wundfläche geschaffen, die das Risiko einer postinterventionellen Infektion sowie einer resultierenden Vernarbung birgt. Die Mehrzahl der Komplikationen nach den ablativen Verfahren beruht auf einer prolongierten Wundheilung und hieraus entstehenden bakteriellen, viralen und fungalen Infektionen. Nicht selten kann es durch die Verletzung der epidermalen und oberen dermalen Schichten zur Reaktivierung von Herpes-simplexVirus(HSV)-Infektionen kommen [17].Die ideale Therapie jeglicher Art von Hautdegeneration sollte daher die Expression epidermaler und dermaler Gene und Proteine steigern, die die Hautregeneration stimulieren und provozieren, ohne dabei die Haut signifikant zu verletzen, und zeitgleich eine postoperative Narbenbildung vermeiden.Der perkutanen Kollageninduktion gelingt es, effektiv Falten und Narben zu behandeln, ohne die Gefahr einer Pigmentierungs-oder Wundheilungsstörung. Bei dieser Methode wird die Epidermis nich...