Inclusion of CYP3A5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation

Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C₀ concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three‐compartment model with first‐order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat‐free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3‐4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.     

Judging roughness by sight—A 7‐tesla fMRI study on responsivity of the primary somatosensory cortex during observed touch of self and others

Observing another person being touched activates our own somatosensory system. Whether the primary somatosensory cortex (S1) is also activated during the observation of passive touch, and which subregions of S1 are responsible for self‐ and other‐related observed touch is currently unclear. In our study, we first aimed to clarify whether observing passive touch without any action component can robustly increase activity in S1. Secondly, we investigated whether S1 activity only increases when touch of others is observed, or also when touch of one's own body is observed. We were particularly interested in which subregions of S1 are responsible for either process. We used functional magnetic resonance imaging at 7 Tesla to measure S1 activity changes when participants observed videos of their own or another's hand in either egocentric or allocentric perspective being touched by different pieces of sandpaper. Participants were required to judge the roughness of the different sandpaper surfaces. Our results clearly show that S1 activity does increase in response to observing passive touch, and that activity changes are localized in posterior but not in anterior parts of S1. Importantly, activity increases in S1 were particularly related to observing another person being touched. Self‐related observed touch, in contrast, caused no significant activity changes within S1. We therefore assume that posterior but not anterior S1 is part of a system for sharing tactile experiences with others. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

High-frequency rTMS of the motor cortex does not influence the nociceptive flexion reflex but increases the unpleasantness of electrically induced pain

The aim of this study was to investigate whether a 10-Hz repetitive transcranial magnetic stimulation (rTMS) applied over the motor cortex, using a stimulus paradigm employed for pain control in chronic pain, affects acute electrically induced pain. We investigated whether rTMS modulates the nociceptive flexion reflex (NFR) in addition to subjective pain perception. Pain threshold, NFR threshold, supra-threshold NFR response, and the concomitant pain intensity and pain unpleasantness visual analogue scale (VAS) scores were compared before and after 20 min of rTMS. Effects of 20 trains of 5 s' duration (55 s intertrain interval) of 10-Hz rTMS at 80% of the resting motor threshold (RMT) applied over the dominant motor cortex were compared to sham rTMS in 12 healthy volunteers. Supra-threshold NFR stimulation significantly increased pain unpleasantness VAS scores with real rTMS compared to sham rTMS (F(1,10)=6.91; P=0.025). There was no significant effect of 10-Hz rTMS on the subjective pain threshold or on the NFR, neither at threshold nor at supra-threshold noxious stimulation. The rTMS paradigm used to control chronic pain is not suitable for controlling Adelta fiber-mediated acute experimentally induced pain since the effects on pain perception were only marginal, with an increase in the VAS unpleasantness scores but with no effect on the NFR. The increased activity of cortico-thalamic projections might modulate the perception of Adelta fiber-mediated pain within the lateral pain pathway. The type of fiber that is stimulated and neuroplastic changes in chronic pain and are thought to be critical for rTMS to have an effect.     

Wissenstransfer zur Reproduktionsmedizin

Background

The Internet in general and digital social networks in particular are increasingly important sources for health information; this also applies to information in the context of treatment of patients wishing for a baby. Initial studies show that patients are not only looking for factual information but also for emotional support. Whether digital social networks add to or compete with classical information and consulting is still unclear.

Methods

In order to provide a preliminary answer to this question, a literature study was conducted to determine relevant empirical findings regarding the use of the Internet and digital social networks. This was done using a keyword search in literature databases and then keyword snowballing.

Results

Information and advice from the Internet and from digital social networks can be seen as an addition to medical expertise, but are not a substitute. Digital social networks, in particular, supplement social peer groups and the relationship with physicians and will become even more important in the future.

Conclusion

For professionals active in the field of reproductive medicine, this could be an indication of deficits with regard to counseling and treatment, which in the future might be countered by providing new services.

     

Direct determination of carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa from positive blood cultures using laser scattering technology

Delays in appropriate antimicrobial treatment contribute to increased mortality of septic patients. We aimed to develop a methodology for detection of carbapenem resistance in Gram-negative bacteria directly from positive blood cultures (BCs). Initially, meropenem-resistant Enterobacteriaceae (n?=?13) and Pseudomonas aeruginosa (n?=?32) isolates as well as the same numbers of meropenem-susceptible isolates were used to establish the detection of carbapenem resistance from agar cultures. Growth-based phenotypic detection of meropenem resistance was performed by a laser scattering (LS) method using a BacterioScan?216R instrument. A subset of the strain collection consisting of meropenem-susceptible and -resistant isolates (each comprising seven P. aeruginosa and three Klebsiella pneumoniae) was used for determination of carbapenem resistance directly from positive BCs. Lysis/centrifugation and filtration/dilution methods were investigated for processing of positive BCs. Four different statistical approaches to discriminate between susceptible and resistant bacteria in real-time were applied and were compared regarding their sensitivity and specificity. After 3?h and 4?h of incubation, respectively, detection of carbapenem resistance in Enterobacteriaceae (sensitivity, 100%; specificity, 100%) and P. aeruginosa (sensitivity, 100%; specificity, ≥90%) agar cultures was attainable. Detection of carbapenem resistance directly from positive BCs was achievable with 100% sensitivity and 100% specificity after 4?h and 5?h, respectively, applying lysis/centrifugation and filtration/dilution methods. In conclusion, LS technology combined with lysis/centrifugation and appropriate statistical real-time analyses represents a promising option for rapid detection of carbapenem resistance in Gram-negative rods directly from positive BCs.     

Airway and systemic inflammatory responses to ultrafine carbon black particles and ozone in older healthy subjects

Increased adverse health effects in older subjects due to exposure to ambient air pollutants may be related to the inflammatory response induced by these contaminants. The aim of this study was to assess airway and systemic inflammatory responses in older healthy subjects to a controlled experimental exposure with spark-generated elemental carbon black ultrafine particles (cbUFPs) and ozone (O₃). Twenty healthy subjects, age 52–75 years, were exposed on three occasions separated by at least 8 weeks. The exposures to filtered air (FA), to cbUFP (50 μg/m³), or to cbUFP in combination with 250 ppb ozone (cbUFP + O₃) for 3 h with intermittent exercise were performed double blind, and in random order. Sputum and blood samples were collected 3.5 h after each exposure. Exposure to cbUFP + O₃ significantly increased plasma club cell protein 16 (CC16), the number of sputum cells, the number and percent of sputum neutrophils, and sputum interleukin 6 and matrix metalloproteinase 9. Exposure to cbUFP alone exerted no marked effect, except for an elevation in sputum neutrophils in a subgroup of 13 subjects that displayed less than 65% sputum neutrophils after FA exposure. None of the inflammatory markers was correlated with age, and serum cardiovascular risk markers were not markedly affected by cbUFP or cbUFP + O₃. Exposure to cbUFP+O₃ induced a significant airway and systemic inflammatory response in older healthy volunteer subjects. The effects induced by cbUFP alone suggest that the inflammation was predominantly mediated by O₃, although one cannot rule out that the interaction of cbUFP and O₃ played a role.