The drug titration paradox: more drug does not correlate with more effect in individual clinical data.

BACKGROUND A fundamental concept in pharmacology is that increasing dose increases drug effect. This is the basis of anaesthetic titration: the dose is increased when increased drug effect is desired and decreased when reduced drug effect is desired. In the setting of titration, the correlation of doses and observed drug effects can be negative, for example increasing dose reduces drug effect. We have termed this the drug titration paradox. We hypothesised that this could be explained, at least in part, by intrasubject variability. If the drug titration paradox is simply an artifact of pooling population data, then a mixed-effects analysis that accounts for interindividual variability in drug sensitivity should 'flip' the observed correlation, such that increasing dose increases drug effect. METHODS We tested whether a mixed-effects analysis could correctly reveal the underlying pharmacology using previously published data obtained during automatic feedback control of mean arterial pressure (MAP) with alfentanil (effect site concentration, CeAlf) during surgery. The relationship between MAP and CeAlf was explored with linear regression and a linear mixed-effects model. RESULTS A linear mixed-effects model did not identify the correct underlying pharmacology because of the presence of the titration paradox in the individual data. CONCLUSIONS The relationship between drug dose and drug effect must be determined under carefully controlled experimental conditions. In routine care, where the effect is profoundly influenced by varying clinical conditions and drugs are titrated to achieve the desired effect, it is nearly impossible to draw meaningful conclusions about the relationship between dose and effect

17-jähriger Mann mit akuten Bauchschmerzen, Hämatochezie und Exanthem

Zusammenfassung: Ein 17-jähriger Patient stellte sich mit kolikartigen abdominellen Schmerzen und Diarrhö vor. Als weitere Symptome traten Petechien, Arthralgien und eine Hämatochezie auf. Sonographisch bestand eine auffällige Ileozökalregion. Endoskopisch fand sich eine Ileitis terminalis, und histologisch zeigte sich hier eine leukozytoklastische Vaskulitis mit IgA-Ablagerungen. Die Kasuistik zeigt exemplarisch die mehrzeitige klinische Manifestation der Purpura Schönlein-Henoch und deren Verlau

Do Irrelevant Sounds Impair the Maintenance of All Characteristics of Speech in Memory?

Several studies have shown that maintaining in memory some attributes of speech, such as the content or pitch of an interlocutor's message, is markedly reduced in the presence of background sounds made of spectrotemporal variations. However, experimental paradigms showing this interference have only focused on one attribute of speech at a time, and thus differ from real-life situations in which several attributes have to be memorized and maintained simultaneously. It is possible that the interference is even greater in such a case and can occur for a broader range of background sounds. We developed a paradigm in which participants had to maintain the content, pitch and speaker size of auditorily presented speech information and used various auditory distractors to generate interference. We found that only distractors with spectrotemporal variations impaired the detection, which shows that similar interference mechanisms occur whether there are one or more speech attributes to maintain in memory. A high percentage of false alarms was observed with these distractors, suggesting that spectrotemporal variations not only weaken but also modify the information maintained in memory. Lastly, we found that participants were unaware of the interference. These results are similar to those observed in the visual modalit

Human Processing of Behaviorally Relevant and Irrelevant Absence of Expected Rewards: A High-Resolution ERP Study

Acute lesions of the posterior medial orbitofrontal cortex (OFC) in humans may induce a state of reality confusion marked by confabulation, disorientation, and currently inappropriate actions. This clinical state is strongly associated with an inability to abandon previously valid anticipations, that is, extinction capacity. In healthy subjects, the filtering of memories according to their relation with ongoing reality is associated with activity in posterior medial OFC (area 13) and electrophysiologically expressed at 220–300 ms. These observations indicate that the human OFC also functions as a generic reality monitoring system. For this function, it is presumably more important for the OFC to evaluate the current behavioral appropriateness of anticipations rather than their hedonic value. In the present study, we put this hypothesis to the test. Participants performed a reversal learning task with intermittent absence of reward delivery. High-density evoked potential analysis showed that the omission of expected reward induced a specific electrocortical response in trials signaling the necessity to abandon the hitherto reward predicting choice, but not when omission of reward had no such connotation. This processing difference occurred at 200–300 ms. Source estimation using inverse solution analysis indicated that it emanated from the posterior medial OFC. We suggest that the human brain uses this signal from the OFC to keep thought and behavior in phase with reality

From Quantum Universal Enveloping Algebras to Quantum Algebras

The ``local'' structure of a quantum group G_q is currently considered to be an infinite-dimensional object: the corresponding quantum universal enveloping algebra U_q(g), which is a Hopf algebra deformation of the universal enveloping algebra of a n-dimensional Lie algebra g=Lie(G). However, we show how, by starting from the generators of the underlying Lie bialgebra (g,\delta), the analyticity in the deformation parameter(s) allows us to determine in a unique way a set of n ``almost primitive'' basic objects in U_q(g), that could be properly called the ``quantum algebra generators''. So, the analytical prolongation (g_q,\Delta) of the Lie bialgebra (g,\delta) is proposed as the appropriate local structure of G_q. Besides, as in this way (g,\delta) and U_q(g) are shown to be in one-to-one correspondence, the classification of quantum groups is reduced to the classification of Lie bialgebras. The su_q(2) and su_q(3) cases are explicitly elaborated.Comment: 16 pages, 0 figures, LaTeX fil

Brain-actuated functional electrical stimulation elicits lasting arm motor recovery after stroke

Brain-computer interfaces (BCI) are used in stroke rehabilitation to translate brain signals into intended movements of the paralyzed limb. However, the efficacy and mechanisms of BCI-based therapies remain unclear. Here we show that BCI coupled to functional electrical stimulation (FES) elicits significant, clinically relevant, and lasting motor recovery in chronic stroke survivors more effectively than sham FES. Such recovery is associated to quantitative signatures of functional neuroplasticity. BCI patients exhibit a significant functional recovery after the intervention, which remains 6–12 months after the end of therapy. Electroencephalography analysis pinpoints significant differences in favor of the BCI group, mainly consisting in an increase in functional connectivity between motor areas in the affected hemisphere. This increase is significantly correlated with functional improvement. Results illustrate how a BCI–FES therapy can drive significant functional recovery and purposeful plasticity thanks to contingent activation of body natural efferent and afferent pathways

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02)

Background: This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma. Patients and methods: Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m2 and docetaxel (Taxotere) 75 mg/m2 on days 1 and 22, followed by radiotherapy of 45 Gy (25 × 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m2 and docetaxel 20 mg/m2 weekly for 5 weeks, followed by surgery. Results: Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications. Conclusions: This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigatio