[S2k guidelines of the PEG on calculated parenteral initial treatment of bacterial diseases in adults : Focussed summary and supplementary information on antibiotic treatment of critically ill patients]. / S2k-Leitlinie der PEG zur kalkulierten parenteralen Initialtherapie bakterieller Erkrankungen bei Erwachsenen : Fokussierte Zusammenfassung und ergänzende Informationen zur Antibiotikatherapie kritisch kranker Patienten.

In January 2018 the recent revision of the S2k guidelines on calculated parenteral initial treatment of bacterial diseases in adults-update 2018 (Editor: Paul Ehrlich Society for Chemotherapy, PEG) was realized. It is a helpful tool for the complex infectious disease setting in an intensive care unit. The present summary of the guidelines focuses on the topics of anti-infective agents, including new substances, pharmacokinetics and pharmacodynamics as well as on microbiology, resistance development and recommendations for calculated drug therapy in septic patients. As in past revisions the recent resistance situation and results of new clinical studies are considered and anti-infective agents are summarized in a table.

[Adequate anti-infective treatment : Importance of individual dosing and application]. / Adäquate Antiinfektivatherapie : Bedeutung der individuellen Dosierung und Applikation.

Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (Vd) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti-infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beta-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine.

[Therapeutic drug monitoring and individual dosing of antibiotics during sepsis : Modern or just "trendy"?] / Therapeutisches Drug Monitoring und individualisierte Dosierung von Antibiotika bei der Sepsis : Modern oder nur "modisch"?

Pharmacokinetic variability of anti-infective drugs due to pathophysiological changes by severe sepsis and septic shock is a well-known problem for critically ill patients resulting in suboptimal serum and most likely tissue concentrations of these agents.To cover a wide range of potential pathogens, high concentrations of broad spectrum anti-infectives have to reach the site of infection. Microbiological susceptibility testing (susceptible, intermediate, resistant) don't take the pharmacokinetic variability into account and are based on data generated by non-critically ill patients. But inter-patient variability in distribution and elimination of anti-infective drugs in ICU patients is extremely high and also highly unpredictable. Drug clearance of mainly renally eliminated drugs and thus the required dose can differ up to 10-fold due to the variability in renal function in patients with severe infections. To assure a timely and adequate anti-infective regime, individual dosing and therapeutic drug monitoring (TDM) seem to be appropriate tools in the setting of pathophysiological changes in pharmacokinetics (PK) and pharmakodynamics (PD) due to severe sepsis. In the case of known minimal inhibitory concentration, PK/PD indices (time or peak concentration dependent activity) and measured serum level can provide an optimal target concentration for the individual drug and patient.Modern anti-infective management for ICU patients includes more than the choice of drug and prompt application. Individual dosing, optimized prolonged infusion time and TDM give way to new and promising opportunities in infection control.

The effects of speed-dependent treadmill training and rhythmic auditory-cued overground walking on balance function, fall incidence, and quality of life in individuals with idiopathic Parkinson's disease: a randomized controlled trial.

OBJECTIVES: The purpose of this single-blinded, randomized controlled study was to examine and compare the immediate and retention effects of progressive speed-dependent treadmill training (SDTT) and rhythmic auditory-cued (RAC) training on balance function, fall incidence, and quality of life (QOL) in individuals with PD. METHODS: Twenty participants (mean age 66.1 yrs) with idiopathic PD were randomized into either SDTT (n = 10) or RAC (n = 10) progressive, interval-based locomotor training for 6 weeks. Measures included the Berg Balance Scale (BBS), Rapid Step-Up Test (RST), Activities-specific Balance Confidence Scale, Parkinson's Disease Questionnaire-39 (PDQ), and the NeuroCom Sensory Organization Test (SOT), Motor Control Test, and Limits of Stability (LOS). Fall incidence was assessed prospectively post-training based on six monthly self-report fall calendars. RESULTS: Significant gains in balance measures were observed post-training in BBS, RST and SOT for the RAC group and in RST, SOT and LOS for the SDTT group. Gains were retained at 3 months post-training in all measures for RAC group, but only the RST for the SDTT group. No clear trend in reduction in fall frequency was evident. CONCLUSION: Externally-cued locomotor training paradigms with progressive speed challenges produced significant improvements in dynamic balance function in persons with PD, with stronger retention of gains in RAC group.

Lack of IL-4 receptor expression on T helper cells reduces T helper 2 cell polyfunctionality and confers resistance in allergic bronchopulmonary mycosis.

T helper (Th)1 and Th2 cells play decisive roles in the regulation of resistance vs. susceptibility to pulmonary cryptococcosis. To study the function of interleukin (IL)-4 receptor (IL-4R) on Th cells in pulmonary cryptococcosis, we infected mice specifically lacking IL-4Rα on CD4(+) T cells (Lck(Cre)IL-4Rα(-/lox) mice) and IL-4Rα(-/lox) controls. Lck(Cre)IL-4Rα(-/lox) mice developed enhanced resistance accompanied by reduced pulmonary allergic inflammation and diminished production of the Th2 cytokines IL-4, IL-5, and IL-13 as compared with IL-4Rα(-/lox) mice. Polyfunctional antigen-specific Th2 cells producing simultaneously two or three Th2 cytokines were reduced in infected Lck(Cre)IL-4Rα(-/lox) mice, pointing to a critical role of polyfunctional Th2 cells for disease progression. Reduced Th2 polyfunctionality was associated with fewer pulmonary alternatively activated macrophages. This work is the first direct evidence for a critical contribution of the IL-4R on Th cells to Th2-dependent susceptibility during allergic bronchopulmonary mycosis. Moreover, the data demonstrate that the quality of the Th2 response has an impact on type 2 inflammation. The analysis of polyfunctional Th2 cells may be useful for monitoring the course of the disease.

Biosensor microprobes with integrated microfluidic channels for bi-directional neurochemical interaction.

This paper reports on silicon-based microprobes, 8 mm long and 250 µm × 250 µm cross-section, comprising four recessed biosensor microelectrodes (50 µm × 150 µm) per probe shank coated with an enzymatic layer for the selective detection of choline at multiple sites in brain tissue. Integrated in the same probe shank are up to two microfluidic channels for controlled local liquid delivery at a defined distance from the biosensor microelectrodes. State-of-the-art silicon micromachining processing was applied for reproducible fabrication of these experiment-tailored multi-functional probe arrays. Reliable electric and fluidic interconnections to the microprobes are guaranteed by a custom-made holder. The reversible packaging method implemented in this holder significantly reduces cost and assembly time and simplifies storage of the biosensor probes between consecutive experiments. The functionalization of the electrodes is carried out using electrochemically aided adsorption. This spatially controlled deposition technique enables a parallel deposition of membranes and is especially useful when working with microelectrode arrays. The achieved biosensors show adequate characteristics to detect choline in physiologically relevant concentrations at sufficient temporal and spatial resolution for brain research. Sensitivity to choline better than 10 pA µm(-1), detection limit below 1 µM and response time of 2 s were obtained. The proposed combination of biosensors and microfluidic injectors on the same microprobe allows simultaneous chemical stimulation and recording as demonstrated in an agarose gel-based brain phantom.

[Biologics. Magic bullets - magic effects - magic costs? New therapeutics and their effects]. / Biologika. Magic bullets - magic effects - magic costs? Neue Therapien und ihre (Aus-)Wirkungen.

Biologics and especially therapeutic monoclonal antibodies have an ever increasing impact in the therapy of inflammatory and malignant diseases. They allow a selective blockade of cytokines, receptors and other molecules. This review summarizes the immunological background, the current state and future trends in the development of these therapeutic agents.

Enzyme-based choline and L-glutamate biosensor electrodes on silicon microprobe arrays.

Brain-implantable microprobe arrays, 6.5 mm shaft-length, incorporating several recessed Pt microelectrodes (50 µm×150 µm) and an integrated Ag/AgCl reference electrode fabricated by silicon micromachining dry etching techniques (DRIE) are described. The microelectrodes are coated by an enzyme membrane and a semi-permeable m-phenylenediamine layer for the selective detection of the neurotransmitters choline and L-glutamate at physiologically relevant concentrations. The functionalisation is based on electrochemically aided adsorption (EAA) combined with chemical co-cross-linking using glutaraldehyde and electrochemical polymerisation, respectively. These deposition methods are fully compatible with the fabricated microprobe arrays for the simultaneous detection of several analytes in different brain target areas. They are spatially controlled and allow fabricating biosensors on several microelectrodes in parallel or providing a cross-talk-free coating of closely spaced microelectrodes with different enzyme membranes. A sensitivity of 132±20 µA mM(-1) cm(-2) for choline and 95±20 µA mM(-1) cm(-2) for L-glutamate with limits of detections below 0.5 µM was obtained. The results of in vitro and in vivo experiments confirm the functional viability of the choline and l-glutamate biosensors.

[Effector function plasticity of T helper lymphocytes]. / Plastizität der Effektorfunktionen von T-Helfer-Lymphozyten.

T helper (Th) cells are grouped into functionally different subsets (considered hitherto distinct and stable) according to their cytokine production. However, a number of recent findings show a much higher degree of Th cell plasticity and interconvertibility than previously assumed. Therefore, Th effector functions might be subject to therapeutic modulation even in late stages of immunopathological diseases.

[Administering drugs to infants, children, and adolescents]. / Arzneimittelanwendung bei Kindern und Jugendlichen.

In many cases, pharmaceutical manufacturers do not embark on lenghty licencing procedures for pediatric medications. Therefore, formulations and dosages suitable for children are often not available, and even medications that have been approved for pediatric use sometimes lack the information and tools required for correct usage. Therefore, choosing a suitable medication that allows for individual dosing, taking into account physiological peculiarities, providing appropriate tools and comprehensive information for parents and/or nursing staff is vital to the success of drug treatments in pediatric patients.

Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen-induced arthritis: influence on T helper cell activation.

To examine the effects of anti-CD4 mAb treatment in acute and chronic antigen-induced arthritis (AIA), C57BL/6 mice were treated intraperitoneally either with the depleting anti-CD4 mAb GK1.5 or with rat-IgG (control) on Days -1, 0, 1, 3, 5, and 7. Arthritis was monitored by assessment of joint swelling and histological evaluation in the acute (Day 3) and the chronic phase (Day 21) of AIA. To determine the effects on cellular immune responses, in vivo T-cell reactivity (delayed type hypersensitivity; DTH) was measured, as well as protein levels of TH1- (IL-2, IFN-gamma) and TH2-cytokines (IL-4, IL-10) in joint extracts and supernatants of ex vivo stimulated spleen and lymph node cells. The humoral immune response was analysed by measuring serum antibodies against methylated bovine serum albumine (mBSA) and extracellular matrix proteins. Treatment with GK1.5 reduced swelling, inflammation, and destruction of the arthritic joint. Unexpectedly, the effects were even more pronounced in the acute than in the chronic phase. The anti-inflammatory effect was accompanied by a diminished DTH against the arthritogen mBSA and a decrease of TH1-cytokine production in spleen and pooled body lymph nodes, whereas the TH2-cytokine production in these organs was unchanged and the humoral immune response was only moderately reduced. There was a failure of depleting CD4+ T-cells in the joint, reflected also by unchanged local cytokine levels. Therefore, systemic rather than local effects on the TH1/TH2 balance appear to underlie the therapeutic efficacy of anti-CD4 treatment in AIA.

Creating a reliable bond. An all-in-one system.

This paper explains the reasons why a new adhesion concept was developed, how it was conceived and what properties and test results were achieved with the product Prompt L-Pop that follows this new concept. Therefore, a short historical introduction into the development of adhesive materials is given followed by a summary of today's state-of-the-art techniques. The requirements for the new adhesion concept are pointed out and the outcome of the effort in the development is explained in more detail. In vitro and in vivo test results of Prompt L-Pop support the new concept by revealing excellent bond strength values in combination with good marginal adaptation and a significantly reduced post operative sensitivity. Finally, further developments regarding the new concept are discussed, such as the use of Prompt L-Pop in combination with plasma curing lights or indirect restorations.